Review ArticleDrug Delivery Systems CNS Protection and theBlood Brain Barrier

Ravi Kant Upadhyay

Department of Zoology DDU Gorakhpur University Gorakhpur 273009 India

Correspondence should be addressed to Ravi Kant Upadhyay rkupadhyayahoocom

Received 27 February 2014 Revised 31 May 2014 Accepted 5 June 2014 Published 20 July 2014

Academic Editor Jianshu Li

Copyright copy 2014 Ravi Kant UpadhyayThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Present reviewhighlights various drug delivery systems used for delivery of pharmaceutical agentsmainly antibiotics antineoplasticagents neuropeptides and other therapeutic substances through the endothelial capillaries (BBB) forCNS therapeutics In additionthe use of ultrasound in delivery of therapeutic agentsbiomolecules such as proline rich peptides prodrugs radiopharmaceuticalsproteins immunoglobulins and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has beenexplained In addition therapeutic applications of various types of nanoparticles such as chitosan based nanomers dendrimerscarbon nanotubes niosomes beta cyclodextrin carriers cholesterol mediated cationic solid lipid nanoparticles colloidal drugcarriers liposomes and micelles have been discussed with their recent advancements Emphasis has been given on the need ofphysiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount ofdrug into the brain for treatment of various neurological diseases and disorders Further strong recommendations are beingmade todevelop nanosized drug carriersvehicles and noninvasive therapeutic alternatives of conventional methods for better therapeuticsof CNS related diseases Hence there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive deliverymethods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs andtreatment methods

1 Introduction

The brain is a highly sensitive and fragile neuronal organ sys-tem that needs a regular supply of fuels gases and nutrientsto maintain homeostasis and other vital functions But BBBa vasculature of the central nervous system acts as a physicalbarrier and imposes various obstacles It inhibits delivery oftherapeutic agents to the CNS [1] and imposes obstructionfor delivery of large number of drugs including antibioticsantineoplastic agents and neuropeptides to pass throughthe endothelial capillaries to brain Though several drugdeliverymethods and strategies have been developed for CNSrelated disease therapeutics most of them are proved invasiveand lack the target specificity More exceptionally all tradi-tional drug delivery methods are based on trials and errorsThese are applied invariably for delivery of few selecteddrugs that had appropriate structure-activity relationshipsor drug-receptor interactions and its structure-transportrelationships are intact [2] However maintaining normal

body functions and transport of various biological substancesincluding therapeutic agents across biological membranes ishighly essential [3] Only few of the existing methods allowdrugs for suitable and successful membrane permeationMoreover new drug delivery methods are developed basedon rational drug design and using high throughput screeningreceptor-ligand interactions to find appropriateness of thedrug among thousands of new compounds Further to reducethe postdelivery toxicity of the drugs noninvasive and lesstoxic drugs and delivery methods have been developedHence a drug should not be selected only after finding highbinding affinity to the receptor in throughput screening butit must be found suitable on the basis of structure-activityrelationships target receptor binding and its behavior inanimal system Though it is possible that it may showinvariably poor membrane permeation properties in vivosuch drugs will undergo insignificant transport through thebrain capillary endothelium whichmakes up the blood brainbarrier (BBB) in vivo [4]

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 869269 37 pageshttpdxdoiorg1011552014869269

2 BioMed Research International

There are so many factors which influence the drugdelivery or its ability to traverse the blood brain barrierHence it is possible that drug may bind to nontransportersin larger amount which render the drug ineffective Sec-ond it seems theoreticallyfalsely active but really it mightshow the inability to pass through the blood brain barrierwith the adhered protein Therefore such drugs cannot bemade available to the brain because they cannot be trans-ported and delivered across the blood brain barrier Furtherenzyme action also makes the drug inactive or convertsit in a nontherapeutic intermediate compound Howeverdue to solubility reasons membrane barriers disallow largermolecules while smaller molecules are carried over to thebrain Similarly charged molecules rapidly get into the brain[5] Therefore lipophilicity does not seem to be necessaryor lonely factor that may assist the drug for safe passageto brain However there seems to be a role of multiplefactors or complex molecular properties that make drugable to pass through the BBB More exceptionally barrierpermeability is also related tomembrane or luminal surface ofbrain capillary composition of CSF or ISF functional groupsand change on molecular and ionic surfaces or presence ofcharged residues of the molecules [6] In addition surfaceactivity of the molecules and its relative size and specificbinding of transporter proteins and energy driven cassettesand opening and closing of ion channels due to ionic concen-tration are key factors which play an important role in drugdelivery [7]

BBB is nonselective to pass drugs by diffusion or byactive transport and creates major hurdles for successful CNSdrug development But it is true that molecules like glucoseand fatlipid soluble drugs can rapidly cross into the brainContrary to this delivery of many of the drug types is verydifficult to carry them into the brain because of fat insolu-ble nature Besides poor membrane permeation propertiesinsignificant transport occurs through the brain capillaryendothelium affecting the drug availability in theoreticallyrelevant concentration [8] Major reasons of therapeuticfailures are slower drug action lesser absorption in neuronaland other brain cells conversion of drug molecule intononinteracting metabolite and association of drug moleculeto other ligands mainly proteins which are nontransportingin nature Though drug remains therapeutically availablein biological system it becomes ineffective or attains someactive molecular form or convert in to a highly reactivemolecular state in the brain This is the main reason whywhen drug passes through the barrier it might adhere to theunwanted protein in larger amounts [9] Further problemmay be created by presence of some catabolic enzymes thatoccur in the brain tissues which could change the nativeform of the drug or cleave it into an inactive moleculeThere is a possibility that an active drug may change into aslow acting drug molecule that may destructed once it getsinside the brain tissue or enzyme catalytic activity renderingit useless Therefore active penetration structure-activityprotection availability dispersion and action of drug intarget area are highly needed for the treatment of variousCNS disorders and diseases Further drug-neuronal receptor

interactions structure-activity relationships and structure-transport relationships that is membrane permeation mustbe evaluated for delivery of any drug into the brain

However several approaches for direct drug deliveryor direct convection-enhanced delivery are used to injectthe drug into brain or cerebrospinal fluid or intranasaldelivery These techniques are highly unsafe invasive localand metabolizable or short lasting Contrary to this thereare safe methods which deliver the drug through vascularroute which infuse and spread in larger portion of the brainHence for therapeutic purposes active transfer of drug ishighly needed For this purpose safer disruption of BBB orits loosening is highly important to deliver the drug into thebrain [10] Therefore for successful delivery of drugs bloodbrain barrier disruption or opening is done by ultrasound andlargely used as intra-arterial infusion therapy It allows boththe chemotherapeutic agents and antibodies to enter throughblood brain barrier [11] Hence BBB dysfunction could be ofgreat therapeutic value in conditions in which neuronal dam-age is secondary or exacerbated by BBB damage Howeverfor therapeutic purposes BBB can be forcibly broken down ordisrupted by ultrasonic soundwaves for safe delivery of drugsor any therapeutic agent to CNS But this forced openingmaylay structural damage to the BBB and allows the uncontrolledpassage of drugs [12] Further it is well known that in severalareas of the brain BBB is very thin or supposed to be looseor weak from where drug can easily pass to the brain Theseareas also allow passage of important metabolic substancesmore freely into the brainThese are identified in Pineal bodyneurohypophysis and area postremaTherefore by reducinghalting or reversing the structure and function of BBB newmethods can be developed for delivery of chemotherapeuticagents in case of brain tumor However in all circumstancesboth drug composition and its delivery methods [13] must beaccounted for making effective drug formulations to treat theCNS disease [8]

So far many different drug delivery methods have beendeveloped Few of them are delivered neurologically invasiveand found unsafe for drug delivery These are neurologicaldirect injections or structural disruption of BBB by usingultrasound Other methods which show broad spectrum anddeliver wide range of drugs to CNS are pharmacological andphysiological methods which are quite safe and noninvasive(Figure 1 Table 1) More specifically neurosurgical strategiesinclude BBB disruption by osmotic imbalance or by usingvasoactive compounds intraventricular drug infusion andintracerebral implants In pharmacological methods lipidcarrier or liposomes are used for drug delivery Physiologicalstrategies are followed by applying endogenous transportmechanisms by using either carrier mediated transport ofnutrients or receptor mediated transport of peptides Fromclinical investigations physiological strategies are provedbetter and potential delivery methods because of widersafety cover provided by drug transport Further conven-tional strategies should be improved for safe delivery ofdifferent drugs to CNS (Figure 2) These include liposomescolloidal drug carriersmicelles chimeric peptide technologyintranasal and olfactory route of administration and nan-otechnologyMore specifically nanoenabled delivery systems

BioMed Research International 3

Tabl

e1Diff

eren

ttyp

esof

drug

deliv

erym

etho

dsus

edforC

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otec

tionan

dtu

mor

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y

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rans

fer

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ntag

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tage

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plications

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particles

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asal

Dire

ctDFlowast

Non

inva

sivea

ndsa

fe

neur

opro

tective

Poor

releas

eofd

rug

Use

ford

eliver

yof

loca

lailm

ents

ofco

ldco

ugh

[34]

Lipid

nano

particles

Intrav

entricular

Dire

ctDF

Enha

nced

rugeffi

cacy

ne

urop

rotective

Toxict

om

embr

anes

Rhin

itisa

ndisc

hem

icbr

aininjuryfor

tum

ora

ndglob

alisc

hem

ia[3

4]

Dire

ctinjection

Intrav

entricular

Dire

ctDF

Less

toxic

impo

sefewer

sidee

ffects

andne

urop

rotective

Inva

sivea

ndtoxic

Use

ford

eliver

yof

pain

med

ication

with

inth

eCSF

[49]

Prod

rugs

Ora

lor

intran

asal

Dire

ctin

direct

DF

Tissue

targ

eted

deliv

eryof

lipop

hilic

molec

uless

afe

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biolog

ical

activ

ityLa

rgely

used

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atne

uron

aldise

ases

[25]

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idem

asking

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ctDF

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lgro

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erse

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rug

thro

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ance

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or[2

8]

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effec

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fea

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rotective

Diffi

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spor

tEff

ectiv

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cerebr

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aira

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a[5

8]

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eric

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ides

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direct

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eted

drug

deliv

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stable

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gtran

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sspe

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ble

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tivei

ntre

atm

ento

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ious

neur

odeg

eneratived

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es[59]

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es

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cont

act

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orde

tectionan

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latio

nlow

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rosis

andlesio

nsNeu

roim

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gof

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dne

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rinet

umor

s[6

0]

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distrib

uted

rug

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rsibly

andne

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rotective

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estruc

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linjury

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eran

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es[6

1]

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[62]

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nism

4 BioMed Research International

Drug delivery for neurological diseases

Drug delivery for neurological disorders

Drug delivery for brain tumors and physical injuries

∙ Meningitis encephalitis virus bacterial protozoan fungal andworm infections

∙ Epilepsy seizures trauma Parkinson multiple sclerosis dementiaAlzheimerrsquos disease mononeuropathy polyneuropathy myopathy

∙ Cerebral tumors cerebrovascular accidents such as thrombosisembolism haemorrhage and vasculitis

Figure 1 Showing important neurological problems which essentially need proper drug delivery for treatment

Intravenousintradermal

intramuscularsubcutaneousIntraventricularintranasal

Topical inhalationOralrectalsublingual

intrathecaltransdermal

Routes of drugdelivery

Figure 2 Showing important routes of drug delivery for CNS therapeutics

offer a promising solution to improve the uptake and targeteddelivery of the drugs into the brain

After delivery of therapeutic biomaterialspharma-ceuticals in the brain its physiological accumulation isneeded that plays a crucial role in the treatment of patho-genesis related to neuronal diseases [14] Another impor-tantfactor in drug delivery is lipid solubility of drug mol-eculescompounds that may move across the blood brainbarrier by simple diffusion There are few compounds whichcould increase the permeability of BBB by loosening thetight junctions between the endothelial cells [15] Mostpsychoactive drugs increase the BBB permeability anddecrease the physical restrictiveness of endothelial tightjunctions and allow most of the therapeutic molecules topass through the BBB in large amounts (Figure 3) Butthese drugs are highly invasive and should give only incontrolled environment because of the risk of multipleeffects Moreover over flooding of molecules in braincauses osmotic imbalances and largely affects membranepermeability and blocks or restricts normal supply ofnutrients Second once tight junctions are loosened thehomeostasis of the brain gets thrown off which resultsin seizures and imposes compromised brain functions[15] However to treat the CNS diseases such as braintumours transport protein peptides radiopharmaceuticalsand other macromolecules are allowed to pass across theblood brain barrier in a controlled concentration For this

purpose nanoparticle delivery methods are proved to bemore promising than any other method available Theseare most usable and noninvasive methods and proved to bemuch better than any other conventional method used forthe treatment of neurological diseases [16] Therefore lesstoxic bioreversible derivatives of prodrugs neurohealersand pharmacological agents are urgently needed Thesemight enable the safe delivery of variety of drugs includinganticancer antineurodegenerative and antiviral drugs Morespecifically more sophisticated nanoparticle based toolsare required for the treatment of brain tumors viral andneurodegenerative diseases and disorders Present reviewarticle aims to emphasize various applications of noninvasivedrug delivery methods with recent developments whichoccurred in nanotherapeutics for CNS protection Hencespecial emphasis has been given to develop nontoxic deliveryvehicles and highly soluble permeable biocompatibleanticancer drugs [17] and liposomal carriers to reduce thetoxic effects and posttreatment fatalities in case of cancer andbrain tumors [17 18] In addition cellular mechanism of drugdelivery such as receptor mediated endocytosis microbubbleenhanced focused ultrasound proline rich peptides chitosanbased nanoparticles beta-cyclodextrin carriers cholesterolmediated cationic solid lipid nanoparticles delivery systemSi RA delivery system colloidal drug carriers liposomes andmicelles have been discussed with their recent advancementsIn addition suggestions have been given for designing much

BioMed Research International 5

BBB

Blood capillary

Endo

Brain Neuronal cells

Neuron

Astrocyte

Synapse envelopedby astrocyte

Dendrite

Neuron

Microglialcells

Cell bodyNucleus

Axon

Axon

Footprocesses

Astrocyte

Oligodendrocyte

Myelin sheath

Figure 3 Showing presence of blood brain barrier at the blood capillary endothelium that obstructs drug delivery to CNS

safer nontoxic delivery vehicles and biocompatible drugs toovercome the problem of clinical failures and posttreatmentfatalities [19]

2 Cancer and Tumor Therapy

Similar to blood brain barrier brain tumor microvesselscapillaries also limit drug delivery to tumors by forminga physical barrier [20] No doubt that TBB is found morepermeable than the blood brain barrier [20 21] but itsignificantly restricts the delivery of anticancer drugs andobstructs systematic chemotherapeutics of brain tumors [22]This causes failure of drug target and makes the processextremely difficult to treat solid tumors in the brain It isthe main reason of clinical failures of many effective andpotential antitumor drugs It is usually not due to the lackof drug potency but rather the nondelivery of drug to thebrain and into the tumors [23] Contrary to this there are fewpharmaceuticals which are used in tumor-specific therapiesthat were found insufficient to check aberrant signaling path-ways in brain tumors [24] It makes the chemotherapeutictreatment ineffective and required amount of drug could notreach into the brain after its delivery [25] Hence it is highlysuggestive that highly toxic antitumor chemotherapeuticdrugs should not be administered in sufficient concentrationby conventional delivery methods because these methodswere not proved to be much helpful to ascertain long termsurvival of the patients with brain tumors andmost of clinicalcases of brain tumors are proving fatal [25] However newwell-designed safer therapeutic strategies that could deliveran appropriate therapeutic concentration of antitumor drug

are to be prepared These should be more responsive fordelivering by applying safer drug delivery systems ormethodsby breaching any physical and physiological obstacle thatexists in the brain [26]

However for making an easy and successful drug deliv-ery to save the life of tumorcancer patients many poten-tial techniques were developed [23] These approaches areintravenous chemotherapy intra-arterial drug delivery localdrug delivery via implanted polymers or catheters BBBdisruption and biochemical modulation of drug [26] Fewother drug delivery methods like intracerebroventricularconvection-enhanced delivery are also proved to be highlyuseful Further to enhance the BTB permeability acceler-ated therapeutic molecules are allowed to pass through itby cellular vasomodulator-mediated transportation mech-anism Thus permeability modulation is possible withoutBBBBTB disruption [27] Interestingly K(Ca) channels werefound to be potential targets for biochemical modulation ofBTB permeability that increases antineoplastic drug deliveryselectively to brain tumors [22] Similarly BTB targetingspecific proteins is also used to increase antineoplastic drugdelivery to brain tumors [27] It accelerates with the for-mation of pinocytic vesicles which assist in transportationof drugs across the BTB It is also accelerated by usingchannel activators [21] Similarly infused minoxidil sulphate(MS) a selective K(ATP) channel activator comes acrossthe BTB to brain tumor and facilitates delivery of certainmacromolecules mainly Her-2 antibody adenoviral-greenflorescent protein and carboplatin to brain tumors [22]It has significantly increased the survival in brain tumorrats Therefore rat brain tumor models are designed totest enhanced drug delivery to brain following intracarotid

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

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[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

2 BioMed Research International

There are so many factors which influence the drugdelivery or its ability to traverse the blood brain barrierHence it is possible that drug may bind to nontransportersin larger amount which render the drug ineffective Sec-ond it seems theoreticallyfalsely active but really it mightshow the inability to pass through the blood brain barrierwith the adhered protein Therefore such drugs cannot bemade available to the brain because they cannot be trans-ported and delivered across the blood brain barrier Furtherenzyme action also makes the drug inactive or convertsit in a nontherapeutic intermediate compound Howeverdue to solubility reasons membrane barriers disallow largermolecules while smaller molecules are carried over to thebrain Similarly charged molecules rapidly get into the brain[5] Therefore lipophilicity does not seem to be necessaryor lonely factor that may assist the drug for safe passageto brain However there seems to be a role of multiplefactors or complex molecular properties that make drugable to pass through the BBB More exceptionally barrierpermeability is also related tomembrane or luminal surface ofbrain capillary composition of CSF or ISF functional groupsand change on molecular and ionic surfaces or presence ofcharged residues of the molecules [6] In addition surfaceactivity of the molecules and its relative size and specificbinding of transporter proteins and energy driven cassettesand opening and closing of ion channels due to ionic concen-tration are key factors which play an important role in drugdelivery [7]

BBB is nonselective to pass drugs by diffusion or byactive transport and creates major hurdles for successful CNSdrug development But it is true that molecules like glucoseand fatlipid soluble drugs can rapidly cross into the brainContrary to this delivery of many of the drug types is verydifficult to carry them into the brain because of fat insolu-ble nature Besides poor membrane permeation propertiesinsignificant transport occurs through the brain capillaryendothelium affecting the drug availability in theoreticallyrelevant concentration [8] Major reasons of therapeuticfailures are slower drug action lesser absorption in neuronaland other brain cells conversion of drug molecule intononinteracting metabolite and association of drug moleculeto other ligands mainly proteins which are nontransportingin nature Though drug remains therapeutically availablein biological system it becomes ineffective or attains someactive molecular form or convert in to a highly reactivemolecular state in the brain This is the main reason whywhen drug passes through the barrier it might adhere to theunwanted protein in larger amounts [9] Further problemmay be created by presence of some catabolic enzymes thatoccur in the brain tissues which could change the nativeform of the drug or cleave it into an inactive moleculeThere is a possibility that an active drug may change into aslow acting drug molecule that may destructed once it getsinside the brain tissue or enzyme catalytic activity renderingit useless Therefore active penetration structure-activityprotection availability dispersion and action of drug intarget area are highly needed for the treatment of variousCNS disorders and diseases Further drug-neuronal receptor

interactions structure-activity relationships and structure-transport relationships that is membrane permeation mustbe evaluated for delivery of any drug into the brain

However several approaches for direct drug deliveryor direct convection-enhanced delivery are used to injectthe drug into brain or cerebrospinal fluid or intranasaldelivery These techniques are highly unsafe invasive localand metabolizable or short lasting Contrary to this thereare safe methods which deliver the drug through vascularroute which infuse and spread in larger portion of the brainHence for therapeutic purposes active transfer of drug ishighly needed For this purpose safer disruption of BBB orits loosening is highly important to deliver the drug into thebrain [10] Therefore for successful delivery of drugs bloodbrain barrier disruption or opening is done by ultrasound andlargely used as intra-arterial infusion therapy It allows boththe chemotherapeutic agents and antibodies to enter throughblood brain barrier [11] Hence BBB dysfunction could be ofgreat therapeutic value in conditions in which neuronal dam-age is secondary or exacerbated by BBB damage Howeverfor therapeutic purposes BBB can be forcibly broken down ordisrupted by ultrasonic soundwaves for safe delivery of drugsor any therapeutic agent to CNS But this forced openingmaylay structural damage to the BBB and allows the uncontrolledpassage of drugs [12] Further it is well known that in severalareas of the brain BBB is very thin or supposed to be looseor weak from where drug can easily pass to the brain Theseareas also allow passage of important metabolic substancesmore freely into the brainThese are identified in Pineal bodyneurohypophysis and area postremaTherefore by reducinghalting or reversing the structure and function of BBB newmethods can be developed for delivery of chemotherapeuticagents in case of brain tumor However in all circumstancesboth drug composition and its delivery methods [13] must beaccounted for making effective drug formulations to treat theCNS disease [8]

So far many different drug delivery methods have beendeveloped Few of them are delivered neurologically invasiveand found unsafe for drug delivery These are neurologicaldirect injections or structural disruption of BBB by usingultrasound Other methods which show broad spectrum anddeliver wide range of drugs to CNS are pharmacological andphysiological methods which are quite safe and noninvasive(Figure 1 Table 1) More specifically neurosurgical strategiesinclude BBB disruption by osmotic imbalance or by usingvasoactive compounds intraventricular drug infusion andintracerebral implants In pharmacological methods lipidcarrier or liposomes are used for drug delivery Physiologicalstrategies are followed by applying endogenous transportmechanisms by using either carrier mediated transport ofnutrients or receptor mediated transport of peptides Fromclinical investigations physiological strategies are provedbetter and potential delivery methods because of widersafety cover provided by drug transport Further conven-tional strategies should be improved for safe delivery ofdifferent drugs to CNS (Figure 2) These include liposomescolloidal drug carriersmicelles chimeric peptide technologyintranasal and olfactory route of administration and nan-otechnologyMore specifically nanoenabled delivery systems

BioMed Research International 3

Tabl

e1Diff

eren

ttyp

esof

drug

deliv

erym

etho

dsus

edforC

NSpr

otec

tionan

dtu

mor

therap

y

Deli

very

vehi

cles

Rout

eoft

rans

fer

Metho

dTM

Adva

ntag

esDisa

dvan

tage

sAp

plications

Referenc

esColloidal

nano

particles

Intran

asal

Dire

ctDFlowast

Non

inva

sivea

ndsa

fe

neur

opro

tective

Poor

releas

eofd

rug

Use

ford

eliver

yof

loca

lailm

ents

ofco

ldco

ugh

[34]

Lipid

nano

particles

Intrav

entricular

Dire

ctDF

Enha

nced

rugeffi

cacy

ne

urop

rotective

Toxict

om

embr

anes

Rhin

itisa

ndisc

hem

icbr

aininjuryfor

tum

ora

ndglob

alisc

hem

ia[3

4]

Dire

ctinjection

Intrav

entricular

Dire

ctDF

Less

toxic

impo

sefewer

sidee

ffects

andne

urop

rotective

Inva

sivea

ndtoxic

Use

ford

eliver

yof

pain

med

ication

with

inth

eCSF

[49]

Prod

rugs

Ora

lor

intran

asal

Dire

ctin

direct

DF

Tissue

targ

eted

deliv

eryof

lipop

hilic

molec

uless

afe

Poor

biolog

ical

activ

ityLa

rgely

used

totre

atne

uron

aldise

ases

[25]

Pept

idem

asking

Injection

Dire

ctDF

RMTlowastlowast

Cholestery

lgro

uptrav

erse

thed

rug

thro

ughBB

BPo

orbiolog

ical

activ

ityM

ultip

lesclero

sisc

ance

rand

tum

or[2

8]

Proteins

Tran

scap

illar

yIn

direct

RMT

Less

toxic

effec

tivea

ndsa

fea

ndne

urop

rotective

Diffi

culttran

spor

tEff

ectiv

eaga

inst

cerebr

alisc

hem

ia

neur

orep

aira

ftert

raum

a[5

8]

Chim

eric

pept

ides

Tran

scap

illar

y$In

direct

RMT

Targ

eted

drug

deliv

ery

stable

durin

gtran

scytos

isLe

sspe

rmea

ble

Effec

tivei

ntre

atm

ento

fvar

ious

neur

odeg

eneratived

iseas

es[59]

Radion

uclid

es

Tran

scap

illar

yIn

direct

DF

cont

act

Tum

orde

tectionan

dab

latio

nlow

dosea

ndne

urop

rotective

Nec

rosis

andlesio

nsNeu

roim

agin

gof

brainan

dne

uroe

ndoc

rinet

umor

s[6

0]

LMEF

Ulowastlowastlowast

Intrav

entricular

Indirect

DF

Non

inva

sive

distrib

uted

rug

reve

rsibly

andne

urop

rotective

Caus

estruc

tura

linjury

Canc

eran

dtu

mor

therap

eutic

sne

urod

egen

eratived

iseas

es[6

1]

Prolin

erich

pept

ides

Tran

scap

illar

yIn

direct

DF

RMT

Less

toxic

safe

andeff

ectiv

ean

dne

urop

rotective

Catalytic

ally

unsta

ble

Use

fort

reatm

ento

fcereb

ralinf

ectio

nsne

uroc

ogni

tived

isord

ers

[62]

lowast

DF

diffu

sionlowastlowast

RMT

rece

ptor

med

iatedtran

scytos

islowastlowastlowast

load

edm

icro

bubb

leen

hanc

edfo

cuse

dultras

ound

$ fl

uorescen

tpro

tein

ra

diop

harm

aceu

ticals

andTM

tra

nspo

rtm

echa

nism

4 BioMed Research International

Drug delivery for neurological diseases

Drug delivery for neurological disorders

Drug delivery for brain tumors and physical injuries

∙ Meningitis encephalitis virus bacterial protozoan fungal andworm infections

∙ Epilepsy seizures trauma Parkinson multiple sclerosis dementiaAlzheimerrsquos disease mononeuropathy polyneuropathy myopathy

∙ Cerebral tumors cerebrovascular accidents such as thrombosisembolism haemorrhage and vasculitis

Figure 1 Showing important neurological problems which essentially need proper drug delivery for treatment

Intravenousintradermal

intramuscularsubcutaneousIntraventricularintranasal

Topical inhalationOralrectalsublingual

intrathecaltransdermal

Routes of drugdelivery

Figure 2 Showing important routes of drug delivery for CNS therapeutics

offer a promising solution to improve the uptake and targeteddelivery of the drugs into the brain

After delivery of therapeutic biomaterialspharma-ceuticals in the brain its physiological accumulation isneeded that plays a crucial role in the treatment of patho-genesis related to neuronal diseases [14] Another impor-tantfactor in drug delivery is lipid solubility of drug mol-eculescompounds that may move across the blood brainbarrier by simple diffusion There are few compounds whichcould increase the permeability of BBB by loosening thetight junctions between the endothelial cells [15] Mostpsychoactive drugs increase the BBB permeability anddecrease the physical restrictiveness of endothelial tightjunctions and allow most of the therapeutic molecules topass through the BBB in large amounts (Figure 3) Butthese drugs are highly invasive and should give only incontrolled environment because of the risk of multipleeffects Moreover over flooding of molecules in braincauses osmotic imbalances and largely affects membranepermeability and blocks or restricts normal supply ofnutrients Second once tight junctions are loosened thehomeostasis of the brain gets thrown off which resultsin seizures and imposes compromised brain functions[15] However to treat the CNS diseases such as braintumours transport protein peptides radiopharmaceuticalsand other macromolecules are allowed to pass across theblood brain barrier in a controlled concentration For this

purpose nanoparticle delivery methods are proved to bemore promising than any other method available Theseare most usable and noninvasive methods and proved to bemuch better than any other conventional method used forthe treatment of neurological diseases [16] Therefore lesstoxic bioreversible derivatives of prodrugs neurohealersand pharmacological agents are urgently needed Thesemight enable the safe delivery of variety of drugs includinganticancer antineurodegenerative and antiviral drugs Morespecifically more sophisticated nanoparticle based toolsare required for the treatment of brain tumors viral andneurodegenerative diseases and disorders Present reviewarticle aims to emphasize various applications of noninvasivedrug delivery methods with recent developments whichoccurred in nanotherapeutics for CNS protection Hencespecial emphasis has been given to develop nontoxic deliveryvehicles and highly soluble permeable biocompatibleanticancer drugs [17] and liposomal carriers to reduce thetoxic effects and posttreatment fatalities in case of cancer andbrain tumors [17 18] In addition cellular mechanism of drugdelivery such as receptor mediated endocytosis microbubbleenhanced focused ultrasound proline rich peptides chitosanbased nanoparticles beta-cyclodextrin carriers cholesterolmediated cationic solid lipid nanoparticles delivery systemSi RA delivery system colloidal drug carriers liposomes andmicelles have been discussed with their recent advancementsIn addition suggestions have been given for designing much

BioMed Research International 5

BBB

Blood capillary

Endo

Brain Neuronal cells

Neuron

Astrocyte

Synapse envelopedby astrocyte

Dendrite

Neuron

Microglialcells

Cell bodyNucleus

Axon

Axon

Footprocesses

Astrocyte

Oligodendrocyte

Myelin sheath

Figure 3 Showing presence of blood brain barrier at the blood capillary endothelium that obstructs drug delivery to CNS

safer nontoxic delivery vehicles and biocompatible drugs toovercome the problem of clinical failures and posttreatmentfatalities [19]

2 Cancer and Tumor Therapy

Similar to blood brain barrier brain tumor microvesselscapillaries also limit drug delivery to tumors by forminga physical barrier [20] No doubt that TBB is found morepermeable than the blood brain barrier [20 21] but itsignificantly restricts the delivery of anticancer drugs andobstructs systematic chemotherapeutics of brain tumors [22]This causes failure of drug target and makes the processextremely difficult to treat solid tumors in the brain It isthe main reason of clinical failures of many effective andpotential antitumor drugs It is usually not due to the lackof drug potency but rather the nondelivery of drug to thebrain and into the tumors [23] Contrary to this there are fewpharmaceuticals which are used in tumor-specific therapiesthat were found insufficient to check aberrant signaling path-ways in brain tumors [24] It makes the chemotherapeutictreatment ineffective and required amount of drug could notreach into the brain after its delivery [25] Hence it is highlysuggestive that highly toxic antitumor chemotherapeuticdrugs should not be administered in sufficient concentrationby conventional delivery methods because these methodswere not proved to be much helpful to ascertain long termsurvival of the patients with brain tumors andmost of clinicalcases of brain tumors are proving fatal [25] However newwell-designed safer therapeutic strategies that could deliveran appropriate therapeutic concentration of antitumor drug

are to be prepared These should be more responsive fordelivering by applying safer drug delivery systems ormethodsby breaching any physical and physiological obstacle thatexists in the brain [26]

However for making an easy and successful drug deliv-ery to save the life of tumorcancer patients many poten-tial techniques were developed [23] These approaches areintravenous chemotherapy intra-arterial drug delivery localdrug delivery via implanted polymers or catheters BBBdisruption and biochemical modulation of drug [26] Fewother drug delivery methods like intracerebroventricularconvection-enhanced delivery are also proved to be highlyuseful Further to enhance the BTB permeability acceler-ated therapeutic molecules are allowed to pass through itby cellular vasomodulator-mediated transportation mech-anism Thus permeability modulation is possible withoutBBBBTB disruption [27] Interestingly K(Ca) channels werefound to be potential targets for biochemical modulation ofBTB permeability that increases antineoplastic drug deliveryselectively to brain tumors [22] Similarly BTB targetingspecific proteins is also used to increase antineoplastic drugdelivery to brain tumors [27] It accelerates with the for-mation of pinocytic vesicles which assist in transportationof drugs across the BTB It is also accelerated by usingchannel activators [21] Similarly infused minoxidil sulphate(MS) a selective K(ATP) channel activator comes acrossthe BTB to brain tumor and facilitates delivery of certainmacromolecules mainly Her-2 antibody adenoviral-greenflorescent protein and carboplatin to brain tumors [22]It has significantly increased the survival in brain tumorrats Therefore rat brain tumor models are designed totest enhanced drug delivery to brain following intracarotid

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

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Diff

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cnan

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theiru

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plicationin

biom

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Com

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ion

Applications

Adva

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n-na

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Chito

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polynu

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Show

low

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unog

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Insu

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rticles

Polym

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nano

particle-cro

ss-li

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bea

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ldeliver

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etarg

eted

treatm

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cros

sbar

rier

Smrh

opr

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edch

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nCoa

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sodium

algina

teor

algina

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lvac

cina

tion

stablea

ndfin

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tac

cessibilitya

ndgo

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mun

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ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 3

Tabl

e1Diff

eren

ttyp

esof

drug

deliv

erym

etho

dsus

edforC

NSpr

otec

tionan

dtu

mor

therap

y

Deli

very

vehi

cles

Rout

eoft

rans

fer

Metho

dTM

Adva

ntag

esDisa

dvan

tage

sAp

plications

Referenc

esColloidal

nano

particles

Intran

asal

Dire

ctDFlowast

Non

inva

sivea

ndsa

fe

neur

opro

tective

Poor

releas

eofd

rug

Use

ford

eliver

yof

loca

lailm

ents

ofco

ldco

ugh

[34]

Lipid

nano

particles

Intrav

entricular

Dire

ctDF

Enha

nced

rugeffi

cacy

ne

urop

rotective

Toxict

om

embr

anes

Rhin

itisa

ndisc

hem

icbr

aininjuryfor

tum

ora

ndglob

alisc

hem

ia[3

4]

Dire

ctinjection

Intrav

entricular

Dire

ctDF

Less

toxic

impo

sefewer

sidee

ffects

andne

urop

rotective

Inva

sivea

ndtoxic

Use

ford

eliver

yof

pain

med

ication

with

inth

eCSF

[49]

Prod

rugs

Ora

lor

intran

asal

Dire

ctin

direct

DF

Tissue

targ

eted

deliv

eryof

lipop

hilic

molec

uless

afe

Poor

biolog

ical

activ

ityLa

rgely

used

totre

atne

uron

aldise

ases

[25]

Pept

idem

asking

Injection

Dire

ctDF

RMTlowastlowast

Cholestery

lgro

uptrav

erse

thed

rug

thro

ughBB

BPo

orbiolog

ical

activ

ityM

ultip

lesclero

sisc

ance

rand

tum

or[2

8]

Proteins

Tran

scap

illar

yIn

direct

RMT

Less

toxic

effec

tivea

ndsa

fea

ndne

urop

rotective

Diffi

culttran

spor

tEff

ectiv

eaga

inst

cerebr

alisc

hem

ia

neur

orep

aira

ftert

raum

a[5

8]

Chim

eric

pept

ides

Tran

scap

illar

y$In

direct

RMT

Targ

eted

drug

deliv

ery

stable

durin

gtran

scytos

isLe

sspe

rmea

ble

Effec

tivei

ntre

atm

ento

fvar

ious

neur

odeg

eneratived

iseas

es[59]

Radion

uclid

es

Tran

scap

illar

yIn

direct

DF

cont

act

Tum

orde

tectionan

dab

latio

nlow

dosea

ndne

urop

rotective

Nec

rosis

andlesio

nsNeu

roim

agin

gof

brainan

dne

uroe

ndoc

rinet

umor

s[6

0]

LMEF

Ulowastlowastlowast

Intrav

entricular

Indirect

DF

Non

inva

sive

distrib

uted

rug

reve

rsibly

andne

urop

rotective

Caus

estruc

tura

linjury

Canc

eran

dtu

mor

therap

eutic

sne

urod

egen

eratived

iseas

es[6

1]

Prolin

erich

pept

ides

Tran

scap

illar

yIn

direct

DF

RMT

Less

toxic

safe

andeff

ectiv

ean

dne

urop

rotective

Catalytic

ally

unsta

ble

Use

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4 BioMed Research International

Drug delivery for neurological diseases

Drug delivery for neurological disorders

Drug delivery for brain tumors and physical injuries

∙ Meningitis encephalitis virus bacterial protozoan fungal andworm infections

∙ Epilepsy seizures trauma Parkinson multiple sclerosis dementiaAlzheimerrsquos disease mononeuropathy polyneuropathy myopathy

∙ Cerebral tumors cerebrovascular accidents such as thrombosisembolism haemorrhage and vasculitis

Figure 1 Showing important neurological problems which essentially need proper drug delivery for treatment

Intravenousintradermal

intramuscularsubcutaneousIntraventricularintranasal

Topical inhalationOralrectalsublingual

intrathecaltransdermal

Routes of drugdelivery

Figure 2 Showing important routes of drug delivery for CNS therapeutics

offer a promising solution to improve the uptake and targeteddelivery of the drugs into the brain

After delivery of therapeutic biomaterialspharma-ceuticals in the brain its physiological accumulation isneeded that plays a crucial role in the treatment of patho-genesis related to neuronal diseases [14] Another impor-tantfactor in drug delivery is lipid solubility of drug mol-eculescompounds that may move across the blood brainbarrier by simple diffusion There are few compounds whichcould increase the permeability of BBB by loosening thetight junctions between the endothelial cells [15] Mostpsychoactive drugs increase the BBB permeability anddecrease the physical restrictiveness of endothelial tightjunctions and allow most of the therapeutic molecules topass through the BBB in large amounts (Figure 3) Butthese drugs are highly invasive and should give only incontrolled environment because of the risk of multipleeffects Moreover over flooding of molecules in braincauses osmotic imbalances and largely affects membranepermeability and blocks or restricts normal supply ofnutrients Second once tight junctions are loosened thehomeostasis of the brain gets thrown off which resultsin seizures and imposes compromised brain functions[15] However to treat the CNS diseases such as braintumours transport protein peptides radiopharmaceuticalsand other macromolecules are allowed to pass across theblood brain barrier in a controlled concentration For this

purpose nanoparticle delivery methods are proved to bemore promising than any other method available Theseare most usable and noninvasive methods and proved to bemuch better than any other conventional method used forthe treatment of neurological diseases [16] Therefore lesstoxic bioreversible derivatives of prodrugs neurohealersand pharmacological agents are urgently needed Thesemight enable the safe delivery of variety of drugs includinganticancer antineurodegenerative and antiviral drugs Morespecifically more sophisticated nanoparticle based toolsare required for the treatment of brain tumors viral andneurodegenerative diseases and disorders Present reviewarticle aims to emphasize various applications of noninvasivedrug delivery methods with recent developments whichoccurred in nanotherapeutics for CNS protection Hencespecial emphasis has been given to develop nontoxic deliveryvehicles and highly soluble permeable biocompatibleanticancer drugs [17] and liposomal carriers to reduce thetoxic effects and posttreatment fatalities in case of cancer andbrain tumors [17 18] In addition cellular mechanism of drugdelivery such as receptor mediated endocytosis microbubbleenhanced focused ultrasound proline rich peptides chitosanbased nanoparticles beta-cyclodextrin carriers cholesterolmediated cationic solid lipid nanoparticles delivery systemSi RA delivery system colloidal drug carriers liposomes andmicelles have been discussed with their recent advancementsIn addition suggestions have been given for designing much

BioMed Research International 5

BBB

Blood capillary

Endo

Brain Neuronal cells

Neuron

Astrocyte

Synapse envelopedby astrocyte

Dendrite

Neuron

Microglialcells

Cell bodyNucleus

Axon

Axon

Footprocesses

Astrocyte

Oligodendrocyte

Myelin sheath

Figure 3 Showing presence of blood brain barrier at the blood capillary endothelium that obstructs drug delivery to CNS

safer nontoxic delivery vehicles and biocompatible drugs toovercome the problem of clinical failures and posttreatmentfatalities [19]

2 Cancer and Tumor Therapy

Similar to blood brain barrier brain tumor microvesselscapillaries also limit drug delivery to tumors by forminga physical barrier [20] No doubt that TBB is found morepermeable than the blood brain barrier [20 21] but itsignificantly restricts the delivery of anticancer drugs andobstructs systematic chemotherapeutics of brain tumors [22]This causes failure of drug target and makes the processextremely difficult to treat solid tumors in the brain It isthe main reason of clinical failures of many effective andpotential antitumor drugs It is usually not due to the lackof drug potency but rather the nondelivery of drug to thebrain and into the tumors [23] Contrary to this there are fewpharmaceuticals which are used in tumor-specific therapiesthat were found insufficient to check aberrant signaling path-ways in brain tumors [24] It makes the chemotherapeutictreatment ineffective and required amount of drug could notreach into the brain after its delivery [25] Hence it is highlysuggestive that highly toxic antitumor chemotherapeuticdrugs should not be administered in sufficient concentrationby conventional delivery methods because these methodswere not proved to be much helpful to ascertain long termsurvival of the patients with brain tumors andmost of clinicalcases of brain tumors are proving fatal [25] However newwell-designed safer therapeutic strategies that could deliveran appropriate therapeutic concentration of antitumor drug

are to be prepared These should be more responsive fordelivering by applying safer drug delivery systems ormethodsby breaching any physical and physiological obstacle thatexists in the brain [26]

However for making an easy and successful drug deliv-ery to save the life of tumorcancer patients many poten-tial techniques were developed [23] These approaches areintravenous chemotherapy intra-arterial drug delivery localdrug delivery via implanted polymers or catheters BBBdisruption and biochemical modulation of drug [26] Fewother drug delivery methods like intracerebroventricularconvection-enhanced delivery are also proved to be highlyuseful Further to enhance the BTB permeability acceler-ated therapeutic molecules are allowed to pass through itby cellular vasomodulator-mediated transportation mech-anism Thus permeability modulation is possible withoutBBBBTB disruption [27] Interestingly K(Ca) channels werefound to be potential targets for biochemical modulation ofBTB permeability that increases antineoplastic drug deliveryselectively to brain tumors [22] Similarly BTB targetingspecific proteins is also used to increase antineoplastic drugdelivery to brain tumors [27] It accelerates with the for-mation of pinocytic vesicles which assist in transportationof drugs across the BTB It is also accelerated by usingchannel activators [21] Similarly infused minoxidil sulphate(MS) a selective K(ATP) channel activator comes acrossthe BTB to brain tumor and facilitates delivery of certainmacromolecules mainly Her-2 antibody adenoviral-greenflorescent protein and carboplatin to brain tumors [22]It has significantly increased the survival in brain tumorrats Therefore rat brain tumor models are designed totest enhanced drug delivery to brain following intracarotid

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

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BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

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for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

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[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

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[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

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30 BioMed Research International

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[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

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[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

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[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

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[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

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[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

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[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

4 BioMed Research International

Drug delivery for neurological diseases

Drug delivery for neurological disorders

Drug delivery for brain tumors and physical injuries

∙ Meningitis encephalitis virus bacterial protozoan fungal andworm infections

∙ Epilepsy seizures trauma Parkinson multiple sclerosis dementiaAlzheimerrsquos disease mononeuropathy polyneuropathy myopathy

∙ Cerebral tumors cerebrovascular accidents such as thrombosisembolism haemorrhage and vasculitis

Figure 1 Showing important neurological problems which essentially need proper drug delivery for treatment

Intravenousintradermal

intramuscularsubcutaneousIntraventricularintranasal

Topical inhalationOralrectalsublingual

intrathecaltransdermal

Routes of drugdelivery

Figure 2 Showing important routes of drug delivery for CNS therapeutics

offer a promising solution to improve the uptake and targeteddelivery of the drugs into the brain

After delivery of therapeutic biomaterialspharma-ceuticals in the brain its physiological accumulation isneeded that plays a crucial role in the treatment of patho-genesis related to neuronal diseases [14] Another impor-tantfactor in drug delivery is lipid solubility of drug mol-eculescompounds that may move across the blood brainbarrier by simple diffusion There are few compounds whichcould increase the permeability of BBB by loosening thetight junctions between the endothelial cells [15] Mostpsychoactive drugs increase the BBB permeability anddecrease the physical restrictiveness of endothelial tightjunctions and allow most of the therapeutic molecules topass through the BBB in large amounts (Figure 3) Butthese drugs are highly invasive and should give only incontrolled environment because of the risk of multipleeffects Moreover over flooding of molecules in braincauses osmotic imbalances and largely affects membranepermeability and blocks or restricts normal supply ofnutrients Second once tight junctions are loosened thehomeostasis of the brain gets thrown off which resultsin seizures and imposes compromised brain functions[15] However to treat the CNS diseases such as braintumours transport protein peptides radiopharmaceuticalsand other macromolecules are allowed to pass across theblood brain barrier in a controlled concentration For this

purpose nanoparticle delivery methods are proved to bemore promising than any other method available Theseare most usable and noninvasive methods and proved to bemuch better than any other conventional method used forthe treatment of neurological diseases [16] Therefore lesstoxic bioreversible derivatives of prodrugs neurohealersand pharmacological agents are urgently needed Thesemight enable the safe delivery of variety of drugs includinganticancer antineurodegenerative and antiviral drugs Morespecifically more sophisticated nanoparticle based toolsare required for the treatment of brain tumors viral andneurodegenerative diseases and disorders Present reviewarticle aims to emphasize various applications of noninvasivedrug delivery methods with recent developments whichoccurred in nanotherapeutics for CNS protection Hencespecial emphasis has been given to develop nontoxic deliveryvehicles and highly soluble permeable biocompatibleanticancer drugs [17] and liposomal carriers to reduce thetoxic effects and posttreatment fatalities in case of cancer andbrain tumors [17 18] In addition cellular mechanism of drugdelivery such as receptor mediated endocytosis microbubbleenhanced focused ultrasound proline rich peptides chitosanbased nanoparticles beta-cyclodextrin carriers cholesterolmediated cationic solid lipid nanoparticles delivery systemSi RA delivery system colloidal drug carriers liposomes andmicelles have been discussed with their recent advancementsIn addition suggestions have been given for designing much

BioMed Research International 5

BBB

Blood capillary

Endo

Brain Neuronal cells

Neuron

Astrocyte

Synapse envelopedby astrocyte

Dendrite

Neuron

Microglialcells

Cell bodyNucleus

Axon

Axon

Footprocesses

Astrocyte

Oligodendrocyte

Myelin sheath

Figure 3 Showing presence of blood brain barrier at the blood capillary endothelium that obstructs drug delivery to CNS

safer nontoxic delivery vehicles and biocompatible drugs toovercome the problem of clinical failures and posttreatmentfatalities [19]

2 Cancer and Tumor Therapy

Similar to blood brain barrier brain tumor microvesselscapillaries also limit drug delivery to tumors by forminga physical barrier [20] No doubt that TBB is found morepermeable than the blood brain barrier [20 21] but itsignificantly restricts the delivery of anticancer drugs andobstructs systematic chemotherapeutics of brain tumors [22]This causes failure of drug target and makes the processextremely difficult to treat solid tumors in the brain It isthe main reason of clinical failures of many effective andpotential antitumor drugs It is usually not due to the lackof drug potency but rather the nondelivery of drug to thebrain and into the tumors [23] Contrary to this there are fewpharmaceuticals which are used in tumor-specific therapiesthat were found insufficient to check aberrant signaling path-ways in brain tumors [24] It makes the chemotherapeutictreatment ineffective and required amount of drug could notreach into the brain after its delivery [25] Hence it is highlysuggestive that highly toxic antitumor chemotherapeuticdrugs should not be administered in sufficient concentrationby conventional delivery methods because these methodswere not proved to be much helpful to ascertain long termsurvival of the patients with brain tumors andmost of clinicalcases of brain tumors are proving fatal [25] However newwell-designed safer therapeutic strategies that could deliveran appropriate therapeutic concentration of antitumor drug

are to be prepared These should be more responsive fordelivering by applying safer drug delivery systems ormethodsby breaching any physical and physiological obstacle thatexists in the brain [26]

However for making an easy and successful drug deliv-ery to save the life of tumorcancer patients many poten-tial techniques were developed [23] These approaches areintravenous chemotherapy intra-arterial drug delivery localdrug delivery via implanted polymers or catheters BBBdisruption and biochemical modulation of drug [26] Fewother drug delivery methods like intracerebroventricularconvection-enhanced delivery are also proved to be highlyuseful Further to enhance the BTB permeability acceler-ated therapeutic molecules are allowed to pass through itby cellular vasomodulator-mediated transportation mech-anism Thus permeability modulation is possible withoutBBBBTB disruption [27] Interestingly K(Ca) channels werefound to be potential targets for biochemical modulation ofBTB permeability that increases antineoplastic drug deliveryselectively to brain tumors [22] Similarly BTB targetingspecific proteins is also used to increase antineoplastic drugdelivery to brain tumors [27] It accelerates with the for-mation of pinocytic vesicles which assist in transportationof drugs across the BTB It is also accelerated by usingchannel activators [21] Similarly infused minoxidil sulphate(MS) a selective K(ATP) channel activator comes acrossthe BTB to brain tumor and facilitates delivery of certainmacromolecules mainly Her-2 antibody adenoviral-greenflorescent protein and carboplatin to brain tumors [22]It has significantly increased the survival in brain tumorrats Therefore rat brain tumor models are designed totest enhanced drug delivery to brain following intracarotid

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

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[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 5

BBB

Blood capillary

Endo

Brain Neuronal cells

Neuron

Astrocyte

Synapse envelopedby astrocyte

Dendrite

Neuron

Microglialcells

Cell bodyNucleus

Axon

Axon

Footprocesses

Astrocyte

Oligodendrocyte

Myelin sheath

Figure 3 Showing presence of blood brain barrier at the blood capillary endothelium that obstructs drug delivery to CNS

safer nontoxic delivery vehicles and biocompatible drugs toovercome the problem of clinical failures and posttreatmentfatalities [19]

2 Cancer and Tumor Therapy

Similar to blood brain barrier brain tumor microvesselscapillaries also limit drug delivery to tumors by forminga physical barrier [20] No doubt that TBB is found morepermeable than the blood brain barrier [20 21] but itsignificantly restricts the delivery of anticancer drugs andobstructs systematic chemotherapeutics of brain tumors [22]This causes failure of drug target and makes the processextremely difficult to treat solid tumors in the brain It isthe main reason of clinical failures of many effective andpotential antitumor drugs It is usually not due to the lackof drug potency but rather the nondelivery of drug to thebrain and into the tumors [23] Contrary to this there are fewpharmaceuticals which are used in tumor-specific therapiesthat were found insufficient to check aberrant signaling path-ways in brain tumors [24] It makes the chemotherapeutictreatment ineffective and required amount of drug could notreach into the brain after its delivery [25] Hence it is highlysuggestive that highly toxic antitumor chemotherapeuticdrugs should not be administered in sufficient concentrationby conventional delivery methods because these methodswere not proved to be much helpful to ascertain long termsurvival of the patients with brain tumors andmost of clinicalcases of brain tumors are proving fatal [25] However newwell-designed safer therapeutic strategies that could deliveran appropriate therapeutic concentration of antitumor drug

are to be prepared These should be more responsive fordelivering by applying safer drug delivery systems ormethodsby breaching any physical and physiological obstacle thatexists in the brain [26]

However for making an easy and successful drug deliv-ery to save the life of tumorcancer patients many poten-tial techniques were developed [23] These approaches areintravenous chemotherapy intra-arterial drug delivery localdrug delivery via implanted polymers or catheters BBBdisruption and biochemical modulation of drug [26] Fewother drug delivery methods like intracerebroventricularconvection-enhanced delivery are also proved to be highlyuseful Further to enhance the BTB permeability acceler-ated therapeutic molecules are allowed to pass through itby cellular vasomodulator-mediated transportation mech-anism Thus permeability modulation is possible withoutBBBBTB disruption [27] Interestingly K(Ca) channels werefound to be potential targets for biochemical modulation ofBTB permeability that increases antineoplastic drug deliveryselectively to brain tumors [22] Similarly BTB targetingspecific proteins is also used to increase antineoplastic drugdelivery to brain tumors [27] It accelerates with the for-mation of pinocytic vesicles which assist in transportationof drugs across the BTB It is also accelerated by usingchannel activators [21] Similarly infused minoxidil sulphate(MS) a selective K(ATP) channel activator comes acrossthe BTB to brain tumor and facilitates delivery of certainmacromolecules mainly Her-2 antibody adenoviral-greenflorescent protein and carboplatin to brain tumors [22]It has significantly increased the survival in brain tumorrats Therefore rat brain tumor models are designed totest enhanced drug delivery to brain following intracarotid

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

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BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

6 BioMed Research International

infusion of bradykinin (Bk) nitric oxide (NO) donors oragonists of soluble guanylate cyclase (SGC) and calciumdependent potassium K(Ca) channels [21] Thus modulationof these channels by specific agonists and agents that produceNO and cGMP in situ is essentially required Moreoverselective opening of blood tumor barrier by a nitric oxidedonor increases survival in rats [28] and affects cerebralblood flow in intracerebral C6 gliomas [29] Contrary tothis water soluble compounds are limited by the surfaceareapermeability of the tumor capillaries [30] Thereforein new methods BBB manipulations are being performedfor safe delivery of drug to the brain These methods arenoninvasive which are used in targeted molecular basedtherapies Further multifunctional magnetic nanoparticlesmagnetic resonance imaging was found to be a highlysuccessful method in cancer therapy [31]

3 Use of Prodrugs

Due to presence of physical obstacles imposed by BBB onlysmall amount of drug passes through barrier and reachesto the brain However lack of suitable transporter proteinslows down the supply of drug into the brain Therefore tomake the normal drugsmedically active lipophilicmoleculesare added which make the drug able to pass through thebarrier Thus drug is released in its original and active forminto the brain However inactive drugs could activate afteraddition of lipophilic molecules Further enzymes due tocatalytic action remove the lipophilic group to release thedrug into its active form More often drugs that cannotpass through the blood brain barrier can deliver into thebrain without disrupting the structural barrier by makingprodrugs These are largely used to treat neuronal diseases[32] Thus prodrugs can enhance the therapeutic efficacy ofdrugs andor reduce adverse effects via differentmechanismsincluding increased solubility improved permeability andbioavailability prolonged half-life and tissue-targeted deliv-ery [33] Hence various prodrug systems such as lipophiliccarriers and receptormediated prodrug delivery systems andgene-directed enzyme prodrug systems are used to deliverdrugs into the brain [34] Further prodrugs which haveno or poor biological activity are chemically modified tohave a pharmacologically active agent which must undergotransformation in vivo to release the active drug [35] Thusactive prodrug may be able to pass through the barrier andthen also repass through the barrier without ever releasingthe drug in its active form

Prodrugs are bioreversible derivatives of drug moleculesthat undergo an enzymatic andor chemical transformationin vivo to release the active parent drugThese are pharmaco-logically active agents that overcome barriers to a drugrsquos use-fulness After delivery to the target site prodrugs exert desiredpharmacological effect [36] More specifically inactive drugsor therapeutic compounds are made active by addition oflipophilic groups These active forms of drug better sneakthrough the blood brain barrier These are designed by usingmost common functional groups that may allow the drugpermeability through the physical or any structural barrier

device [36] Prodrugs are used in cancer therapies includingantibody-directed enzyme prodrug therapy (ADEPT) andgene-directed enzyme prodrug therapy (GDEPT) [35] Othermajor applications of the prodrug strategy are the ability toimprove oral absorption and aqueous solubility increase inlipophilicity and active transport and achieve site-selectivedelivery [35] These most favoring parameters are essentiallyrequired in drug discovery and drug development [36] Inpresent time about 7ndash10 of drugs are prodrugs these areprovedto be an effective tool for improving physicochem-ical biopharmaceutical or pharmacokinetic properties ofpharmacologically active agents Further improvements inbasic prodrug design could be made by functional groupconsiderations to drug metabolism involving cytochromeP450 enzymes It will increase water solubility bioavailabilitypermeability and stability to tumor targeting It will alsoassist in the development of new anti-inflammatory anti-HIVagents Thus by using transporters and receptor mediatedendocytosis genes enzymes and activated prodrugs could bedelivered to cancer cells and metastatic tissues [37]

4 Peptide Masking

Further major obstacle to targeting the brain with therapeu-tics in general (PP drugs amongst them) is the presence ofvarious barriers As it is known that blood brain barrier (BBB)controls the concentration and entry of solutes into the CNSHowever for successful permeability PP drug lipophilicityis required that could be achieved by addition of cholesterylgroup thatmakes them able to pass through BBBThese couldbe delivered by following intraventricular administration orany other noninvasive method However for safe carriageof pharmaceuticals another useful way is masking the drugsby converting its chemical composition into a lipid solubledrug However by combining with other molecular groupspeptidersquos basic characteristics are masked and addition of alipophilic group makes it likely to pass through the bloodbrain barrier Hence a cholesteryl molecule is used instead ofcholesterol because of its lipophilic nature It serves to concealthe water soluble characteristics of the drug and such type ofmasking assists the drug in traversing the blood brain barrierSimilar masking of drug peptide from peptide degradingenzymes also occurs in the brain [32] However shorterpeptides with good surface charge may bind to the receptorson one side and mask the no passage of larger moleculesHowever a target molecule could be attached to the drugthat can easily pass the drug through the BBB It can increasethe drug uptake by the brain Further it may degrade in sucha way that the drug cannot pass back through the brainThus for complete prohibition of drug reverse transportit should be converted into a nontransport form and mustconcentrate in the brain for better therapeutic action [32]In addition the drug must be enzymatically degradable thatcould prevent the overdose to the brain tissue or its removalcould minimize the overaction of drug on nervous tissueHence both dosage effect and drug action require intensemonitoring [32] Similarly C-terminal peptide thioestersalso assist in peptide masking These also affect aminolysis

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

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drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

hics

heetsr

olledin

tosin

gleo

rm

ultiw

alledtu

beslt

10nm

predict

emiss

ionfre

quen

cies

bright

eran

dsta

bles

igna

lint

ensit

yco

njug

atet

opr

oteins

fort

arge

ting

com

pose

dof

cyto

toxich

eavy

metals

unstab

lein

UV

radiation

Use

din

vitro

labe

lingof

liver

cells

fluo

rescen

tassay

sto

detect

antig

enso

nce

llsu

sedin

vivo

canc

erde

tection

anddiag

nosis

Mor

estables

igna

lsth

anflu

ores

cent

molec

ulesb

right

erc

anbind

with

proteins

Den

drim

ers

5ndash20

nmhi

ghly

bran

ched

mac

rom

olec

ules

synt

hesiz

edth

roug

hpo

lym

erizationreac

tion

grow

ingou

twardfro

mac

entral

core

5ndash10

bra

nche

dstr

uctu

reallowsh

ighdr

ugca

rriage

Caus

edos

eand

surfa

cech

arge

depe

nden

them

olys

iscy

totoxicinvitro

targe

tedde

liver

yof

drug

sin

aque

ouss

pace

with

inlip

osom

eori

nterca

lated

into

lipid

bilay

ers

used

inge

nede

liver

y

Show

polym

erization

term

inal

grou

psca

nbe

mod

ified

ford

rugtarg

etin

gsh

owhi

ghdr

ugca

rriage

Fulle

rene

s15

ndash500

0leng

than

d05ndash

20diam

eterv

erysim

ilart

oca

rbon

nano

tube

sanex

tend

ed120587

conjug

ated

carb

onsk

eletons

Vapo

rizationof

grap

hites

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ullerene

s13

Clabe

ledfu

llerene

saz

afullerens

Highe

rdru

gde

liver

yforb

rain

tum

ors

BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

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[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

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[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

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[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

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[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 7

of peptides by the secondary amines used for removal ofthe Fmoc group However backbone amide linker (BAL)strategy is followed for their synthesis in which the thioesterfunctionality is masked as a trithioortho ester throughoutthe synthesis [38] It would enhance the effectiveness anddelivery of drug This double-masking of albuterol add-ontherapy is used for patients with multiple sclerosis Similarlytreatment with glatiramer acetate plus albuterol is found tobe well tolerated and improves clinical outcomes in patientswith multiple sclerosis But cholesterol masks membraneglycosphingolipid tumor-associated antigens to reduce theirimmunodetection in human cancer biopsies [39] Contraryto this unmasking by permeabilizing but nondetachingtreatment with cholesterol-binding detergents digitonin andedelfosine compares with and overlaps that of PAO pheny-larsine oxide [40] However depletion of the surface sites byN-terminally clippedY2 agonists indicates larger accessibilityfor a short highly helical peptide It shows the presence of adynamic masked pool including majority of the cell surfaceY2 receptors in adherent CHO cells [40] However in spite oftheir potential many existing peptide and protein drugs (PPdrugs) are rendered ineffective in the treatment because oftheir inability to deliver and sustainability within the brainFor high accessibility masking molecules should be of lowmolecular weight of 400ndash500Da so that they can easily crossthe BBB and deliver the drug in pharmacologically significantamounts [32 41 42]

5 CNS Protection

51 Intranasal Delivery of Drugs There are so many drugsthat reach the CNS after nasal administration in differentanimalmodels as well as in humans [43] (Figure 2) Howeverto deliver sizable amount of drug into the brain intranasaladministration of neuroprotective agents is found to be moreuseful for the treatment of ischemic brain injury It is apreferable method used to deliver local ailments of coldcough rhinitis and so forth [44] Further to accelerate theaction of drug colloidal nanoparticles mucosal or tumorbarrier intranasal delivery method is applied to send themto various parts of brain But delivery of peptides andproteins seems to be very hard to send them for systemic usethrough nasal route [44] Moreover for delivery of peptideand proteins various more appropriate nanoparticles arerequired [44] When a nasal drug formulation is delivereddeep and high enough into the nasal cavity it reachesto olfactory mucosa and transport into the brain andorCSF via the olfactory receptor neurons It should generategood immune response due to preferential interaction tothe lymphoid tissue of the nasal cavity (NALT) Howeverdrug transport through olfactory epithelium [45] shouldwork as a conduit for transmission of drugs to the CNSbut drug transfer in animals show substantially differentratios of olfactory-to-respiratory epithelium than humans[46] Moreover two possible routes that is the olfactorynerve pathway (axonal transport) and the olfactory epithelialpathway [47] are followed by the drugs to reach into thebrain Moreover soon after nasal delivery of a drug it first

reaches to the respiratory epithelium where it absorbed intothe systemic circulation by trans-cellular and para cellularpassive absorption or by transcytosis or endocytosis [4748] However absorption across the respiratory epithelium isthe major transport pathway for nasally administered drugsIt may represent a potentially time saving route for theadministration of certain systemic drugs delivered in cryon-ics medication protocols (eg epinephrine or vasopressin)But sometimes BBB-mediated exclusion of brain-therapeuticagents also remains unsuccessful and drug is found tobe diffused in unwanted regions Hence to overcome thisproblem carbopol-based gels are made for nasal delivery ofbiopharmaceuticals [49]

However intranasal administration of NAD+ is found tobe neuroprotective as it decreases transient focal ischemia[50] Similarly intranasal administration of the PARGinhibitor gallotannin also decreases ischemic brain injuryin rats [51] Such agents abolish activation of poly(ADP-ribose) polymerase-1 (PARP-1) which plays a significant rolein ischemic brain damage Further NAD+ was observedto reduce infarct formation by up to 86 even whenadministered at 2 hours after ischemic onset [51] Similarlyintranasal administration of antiporters or NMDA receptorblockers provides neuroprotection against themore upstreamevents of global ischemia such as membrane depolarizationand excitotoxicity [52] Similarly nasal administration ofEPO (erythropoietin) is a potential novel neurotherapeuticapproach in the treatment of acute ischemic stroke in humans[53] It is one of the most successful methods that showneuroprotective capacity in the treatment of patients withacute stroke and other neurodegenerative disorders Nodoubt that this new therapeutic approach could revolutionizethe treatment of neurodegenerative disorders in the 21stcentury [53]

Moreover brain possesses two drug passing routes fortransportation of substances one is axonal transport thatranges from 20ndash400mmday to a slower 01ndash4mmday [54]It is considered to be a slow route whereby an agent enters theolfactory neuron via endocytotic or pinocytotic mechanismsand travels to the olfactory bulb by utilizing the same antero-grade axonal transport mechanisms Cell uses transportendogenous substances to the brain by this mechanism [47]The epithelial pathway is a significantly faster route for directnose-to-brain transfer whereby compounds pass paracellu-larly across the olfactory epithelium into the perineural spacewhich is continuous with the subarachnoid space and indirect contact with the CSF Then the molecules can diffuseinto the brain tissue or will be cleared by the CSF flow intothe lymphatic vessels and subsequently into the systemiccirculation [45 55] Similarly nasal spray method couldincrease the quantity of VIP (vasoactive intestinal peptide)entering the brain and protect the central nervous systemHence drugs sent through intranasal route cause minorirritation which resolve spontaneously within a week at theend of the treatment [56] More often intranasal delivery is anoninvasive safe (Figure 2 Table 1) and alternative approachwhich rapidly targets delivery of molecules to the brain whileminimizing systemic exposure [57]

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

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Diff

eren

ttyp

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cnan

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theiru

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andap

plicationin

biom

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Com

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Applications

Adva

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Chito

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polynu

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tone

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rtm

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Show

low

imm

unog

enicity

Insu

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rticles

Polym

eric

nano

particle-cro

ss-li

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bea

dsOra

ldeliver

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insu

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cells

Ove

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tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

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edch

itosa

nCoa

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sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

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tac

cessibilitya

ndgo

odim

mun

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soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

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y

Chito

san-

Plur

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nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

8 BioMed Research International

52 Intraventricular Drug Delivery Intraventricular drugdelivery is used for pain medication and drug is deliveredwithin the cerebrospinal fluid of the cistern (C1-2 vertebra)and intracranial ventricles This method is primarily usedfor delivery of analgesic drugs for patients having tumorsof head face and neck More often it is used in cerebraldrug targeting [63] by administering medication directly Itneeds less amount of drug and imposes fewer side effects thanorally administered drugs In this methods a plastic reservoiris used which is implanted subcutaneously in the scalp andconnected to the ventricles within the brain by an outletcatheter Thus medicine is delivered through this implantedcatheter connected to a pump that may be programmableand either implanted or external For example insulin isdirectly targeted into the brain via intracerebroventricular(ICV) or intraparenchymal delivery (Figure 2) It is an inva-sive technique with significant risk necessitating repeatedsurgical intervention and providing potential for systemichypoglycemia [57] This method aids in clinical therapeuticsof associated neurodegenerative and neurovascular disorders(Figure 1) [57]

Similarly intraventricular delivery of rituximab activatescomplements C3 and C5b-9 in CSF It shows an improvedefficacy of intraventricular immunotherapy both via mod-ulation of the innate immune response and innovations indrug delivery [64] Similarly intraventricularv injections offolate receptor-120572-positive and -negative exosomes intomousebrains demonstrate folate receptor-120572-dependent delivery ofexosomes into the brain parenchyma [57] Furthermorevascular endothelial growth factor promotes pericyte cov-erage of brain capillaries that improve cerebral blood flowduring subsequent focal cerebral ischemia and preserves themetabolic penumbra [65] It also enhances cerebral bloodflow during subsequent ischemic episodes leading to thestabilization of cerebral energy state It is possible that itinduces the formation of new vessels and improves braintissue survival [66] Similarly hypothalamic neuron-derivedneurotrophic factor acts as a novel factor which modulatesappetite food intake body weight increased hypothalamicPomc and Mc4r mRNA expression [67] Importantly theappetite-suppressing effect of NENF was abrogated in obesemice fed a high-fat diet demonstrating a diet-dependentmodulation of NENF function [68] Similarly antiangiogenicpigment epithelium-derived factor (PEDF) a multifunctional50 kD secreted glycoprotein promotes stemness by upreg-ulation Moreover intraventricular injection of PEDF pro-motes stem cell renewal while injection of VEGF initiatesdifferentiation and neurogenesis in the subventricular zone[69] Hence enhancing the expression of PEDF in stem cellshas promising therapeutic implications because this proteinpossesses several bioactivities in nearly all normal organsystems It will be an essential component in the developmentand delivery of novel stem cell-based therapies to combatdisease [68]

Similarly intraventricular delivery of vancomycin isused to treat meningitis ventriculitis and CNS associatedinfections However disposition of vancomycin within CNSaids in the improvement of pathophysiological conditions

strokes and injuries that will facilitate in better under-standing of the effects on pharmacokinetic and pharma-codynamic parameters of neuroactive drugs in adults [68]Further it is proved by fluorescence microscopy studiesthat FITC-D3 accumulates in the vacuolar compartmentsof the cells and can be detected in various structures andpopulations of cells after injection into the brain Similarlyconvection-enhanced delivery into the putamennucleus [70]PDA pressure support surfactant therapy inotropic drugadministration vaginal delivery neonatal resuscitation andantenatal corticosteroid therapy could be more significantlyused higher in cases with IVH (intraventricular hemorrhage)[71] It is mainly used to treat hyaline membrane disease andpreeclampsia in mother [60] Similarly intravenous intrac-erebroventricular or intranasal administration of siRNA toneurons glia and brain capillary endothelial cells (BCECs)is used to treat neurological diseases [72] Gene silencingtherapies are also used to deliver short interfering RNA(siRNA) into central nervous system (CNS) while polylysinedendrimers D3 and D5 [73] and melittin-grafted HPMA-oligolysine based copolymers are also used for gene deliv-ery [73] Similarly melittin-containing polyplexes are alsofound to be promising biomaterials for gene delivery tothe brain [73] Moreover Gd-DTPA diffusion in gliomascould assist in real-time monitoring of interstitial drugdelivery and quantitative assessment of biophysical structuralvariations in diseased tissue [73] Further G4 PAMAMdendrimer distribution patterns in the CNS may facilitatethe design of tailored nanomaterials in light of future clinicalapplications It does not induce apoptotic cell death ofneural cells in the submicromolar range of concentrationand induces low microglia activation in brain tissue aftera week [74]

53 Use of Peptide Radiopharmaceuticals Radiolabeledreceptor-binding peptides and proteins have emerged asan important class of radiopharmaceuticals that havechanged radionuclide imaging in clinical practiceThese haveincreased the diagnostic potential of neuroimaging tech-nology and are proved to be a more sophisticated diagnostictool to scan brain for Alzheimerrsquos disease More importantlyin brain imaging small-molecule radio chemicals that bindto monoamine or amino acid neurotransmitter systems areused For example epidermal growth factor (EGF) peptideradiopharmaceuticals were found to be potential candidatesfor neuroimaging which are used for early detection ofmalignant gliomas or brain tumors [75 76] Similarly PETimaging is also used for detection of neuroendocrine tumors[77] in which heterodimeric molecule is used for primaryand recurrent prostate cancer covering These two receptorentities might lead to an improved diagnostic sensitivityand therapeutic efficiency [78] Similarly peptide-based(18)F-radiopharmaceuticals (Table 1) are used for diagnosticapplications with positron emission tomography (PET)in clinical trials [73] In addition tailored gallium (III)bioconjugation is also widely used in preclinical Ga-68-PETImaging [79]

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

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Diff

eren

ttyp

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cnan

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theiru

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andap

plicationin

biom

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Com

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Applications

Adva

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Chito

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polynu

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tone

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rtm

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Show

low

imm

unog

enicity

Insu

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rticles

Polym

eric

nano

particle-cro

ss-li

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bea

dsOra

ldeliver

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insu

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cells

Ove

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tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

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edch

itosa

nCoa

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sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

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tac

cessibilitya

ndgo

odim

mun

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soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

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y

Chito

san-

Plur

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nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

BioMed Research International 9

However for neuroimaging many strategies have beendeveloped to radiolabel peptides and proteins with fluorine-18 It is a more straightforward approach based on thechelation of aluminum fluoride by (147-triazacyclononane-147-triacetic acid) Thus use of Al(18)F labeling technologyhas optimized yield and specific activity and neuroimag-ing potential of peptides [80] NOPO-functionalized pep-tides provide suitable pharmacokinetics in vivo [81] Inaddition inverse electron-demand Diels-Alder click chem-istry is used to develop novel radiopharmaceuticals [82]Similarly chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of theCu(I)-catalyzed conjugation reactionMoreover nucleophilicdetagging and fluorous solid-phase extraction method pro-vides an easy way to implement an approach for obtaining 2-[(18)F] fluoroethyl azide [83] Similarly development of A120573peptide radiopharmaceutical combined with a nanocarrierworks as molecular Trojan horse and has wider applicationsin vivo amyloid imaging in Alzheimerrsquos disease [84] Sim-ilarly (99m) Tc-peptide-ZHER2342 molecular probe is apromising tracer agent used for visual detection of cancer[85] Similarly (131)I-tRRL small peptide because it specif-ically binds to tumor-derived endothelial cells [62] More-over Tc-EDDAHYNIC-E-[c(RGDfK)]2 obtained from kitformulations showed high tumour uptake in patients withmalignant lesions It is a promising imaging marker that isused for targeting site-specific breast cancer [86] Moreover(18)F-glyco-RGD peptides are used in PET imaging of inte-grin expression modulation and biodistribution Recentlyintegrins have become increasingly attractive targets formolecular imaging of angiogenesis with positron emissiontomography or single-photon emission computed tomog-raphy but the reliable production of radiopharmaceuticalsremains challenging [87]

It is very difficult to map the functional connectivity ofdiscrete cell types in the intact mammalian brain duringbehavior Cell type based designer receptor maps exclusivelyprepared by seeing their interactions using designer drug(DREADD) technology could clearly differentiate betweenbrain functions in normal and disease states Hence behav-ioral imaging with 120583PET and [18F] fluorodeoxyglucose(FDG) can generate whole-brain metabolic maps of cell-specific functional circuits during the awake and freelymoving state More often DREAMM could reveal discretebehavioral manifestations and concurrent engagement ofdistinct corticolimbic networks associatedwith dysregulationof Pdyn and Penk in MSNs of the NAcSh DREAMM isa highly sensitive molecular high-resolution quantitativeimaging approach that could clear any brain disorder [88]PET imaging of tumors with a 64Cu labeled macrobicycliccage amine ligand tethered to Tyr3-octreotate MeCOSar isa promising bifunctional chelator for Tyr3-octreotate thatcould be applied to a combined imaging Thus therapeuticregimen can be prepared by using a combination of (64)Cu-and (67) and CuSarTATE complexes owing to improvedtumour-to-nontarget organ ratios compared to (64)CuDO-TATATE at longer time points [89] PET with 62Cu-ATSMand 62Cu-PTSM is a useful imaging tool for hypoxia and

perfusion in pulmonary lesions [58] Further amount of(18)F-FDG uptake is determined by the presence of glucosemetabolism hypoxia and angiogenesis [90 91]

54 Use of Protein Neurotherapeutic Agents BBB restrictsentry of many potentially therapeutic agents (PNA) into thebrain But recently several neuroactive proteins of potentialtherapeutic value have highlighted the crucial need foreffective and safe transcapillary deliverymethods to the brainHowever most promising drug delivery is possible by aug-mentation of pinocytotic vesicles through brain capillariesThis is a cellular mechanism which assists in delivering largemolecules of neurotherapeutic potential in conjugated formlike peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transport(PNA) in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found to be functionally activeand effective in animal models of neurological disease Infact all neuroprotective small molecules have failed to repairstroke in clinical trials because either these molecules haveunfavorable safety profiles or the drugs do not cross the BBBWhen properly delivered these provide neuroprotection upto 3 hours after stroke during which BBB remain intact [92]These short peptides showed favorable safety profiles in brainafter coming cross the BBB [93] For example neurotrophin abrain derived neurotrophic factor (BDNF) is reformulated toenable BBB transport Similarly BDNF chimeric peptide wasfound to be neuroprotective following delayed intravenousadministration in either regional or global brain ischemia[92ndash96] Similarly erythropoietin a novel neurotherapeu-tic agent [97] is also a primary physiological regulator oferythropoiesis [97] exerts effect by binding to cell surfacereceptors and displays hormonal role It is produced by thekidney in response to hypoxic stress and signals the bonemarrow to increase the number of circulating erythrocytes[98] In addition both erythropoietin and its receptor foundin the human cerebral cortex astrocytes and neurons thatare members of a cytokine superfamily mediate diversefunctions in nonhematopoietic tissues It shows neuropro-tective activity that is upregulated following hypoxic stimuliSimilarly in animal models exogenous recombinant humanerythropoietin was proved to be beneficial in treating globaland focal cerebral ischemia and reducing nervous systeminflammation in experimental animals [99] Erythropoietindramatically reduces postinfarct inflammation and showshealing effect in brain and repairs spinal cord injuries such asmechanical trauma experimental autoimmune encephalitisor subarachnoid hemorrhage It directly modulates neuronalexcitability and acts as a trophic factor for neurons in vivoand in vitro It shows dose-dependent effects and is highlybeneficial in epileptic or degenerative neurologic diseases[100] because erythropoietin generates potential impact onbiodistribution of drug and shows fast action mechanismwhen it passes through BBB [100] Therefore pharmaco-logical exploitation of erythropoietic agents could providetherapeutic benefits in CNS dysfunction [100] Howeverdelivery of anthraquinone-2-sulfonic acid (AQ2S) acts as anovel neurotherapeutic agent against cerebral ischemia that

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

hics

heetsr

olledin

tosin

gleo

rm

ultiw

alledtu

beslt

10nm

predict

emiss

ionfre

quen

cies

bright

eran

dsta

bles

igna

lint

ensit

yco

njug

atet

opr

oteins

fort

arge

ting

com

pose

dof

cyto

toxich

eavy

metals

unstab

lein

UV

radiation

Use

din

vitro

labe

lingof

liver

cells

fluo

rescen

tassay

sto

detect

antig

enso

nce

llsu

sedin

vivo

canc

erde

tection

anddiag

nosis

Mor

estables

igna

lsth

anflu

ores

cent

molec

ulesb

right

erc

anbind

with

proteins

Den

drim

ers

5ndash20

nmhi

ghly

bran

ched

mac

rom

olec

ules

synt

hesiz

edth

roug

hpo

lym

erizationreac

tion

grow

ingou

twardfro

mac

entral

core

5ndash10

bra

nche

dstr

uctu

reallowsh

ighdr

ugca

rriage

Caus

edos

eand

surfa

cech

arge

depe

nden

them

olys

iscy

totoxicinvitro

targe

tedde

liver

yof

drug

sin

aque

ouss

pace

with

inlip

osom

eori

nterca

lated

into

lipid

bilay

ers

used

inge

nede

liver

y

Show

polym

erization

term

inal

grou

psca

nbe

mod

ified

ford

rugtarg

etin

gsh

owhi

ghdr

ugca

rriage

Fulle

rene

s15

ndash500

0leng

than

d05ndash

20diam

eterv

erysim

ilart

oca

rbon

nano

tube

sanex

tend

ed120587

conjug

ated

carb

onsk

eletons

Vapo

rizationof

grap

hites

Heterof

ullerene

s13

Clabe

ledfu

llerene

saz

afullerens

Highe

rdru

gde

liver

yforb

rain

tum

ors

BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

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[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

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[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

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[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

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[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

10 BioMed Research International

protects the brain from strokes and neurological diseases[59 101]

Besides neuroprotective compounds monoclonal anti-bodies are also used as novel neurotherapeutic agents torepair CNS injury caused by trauma or hyperthermia [102]In such injuries level of serotonin (5-HT) dynorphin A(Dyn A 1ndash17) nitric oxide synthase (NOS) and tumornecrosis factor-120572 (TNF-120572) increases that also acts as potentialneurodestructive signals in the CNS injury Thus for neu-tralization of these agents monoclonal antibodies directedagainst 5-HT NOS Dyn A (1ndash17) and TNF-120572 in vivo canbe used for neuroprotection and to enhance the neurorepairafter trauma [102] Similarly activation of the nuclear factorE2-related factor 2antioxidant response element pathwayis neuroprotective after spinal cord injury [103] SimilarlyEpo and the Epo receptor (EpoR) play a critical role inneurodevelopment neuroregulation and neuroprotection Itameliorates and prevents neuronal injury and shows neu-roprotective antiapoptotic anti-inflammatory antioxidantangiogenic neurogenic and neurotrophic effects in cellculture and animal models [98]

Similarly metallothioneins (MTs) is a superfamily ofhighly conserved low molecular weight polypeptides whichare characterized by high contents of cysteine (sulphur) andmetals These are intracellular metal-binding proteins whichplay a significant role in the regulation of essential metals[104] In both central and peripheral nervous tissues MT-IandMT-II have neuroprotective roles which are also inducedby exogenous MT-I andor MT-II treatment Both MT-Iand MT-II may provide neurotherapeutic targets offeringprotection against neuronal injury and degeneration [104]In addition metallo-complexes formed inside brain maypossess enough potential for treatment of neurodegenerativediseases [105] Similarly testosterone shows neuroprotectiveeffects on morphology in both males and females It also actsas a neurotherapeutic agent in the injured nervous system[106] Similar to testosterone androgen also regulates neuritinmRNA levels in an in vivo model of steroid-enhancedperipheral nerve regeneration [107] Similarly indomethacin-loaded lipid-core nanocapsules reduce the damage triggeredby A1205731ndash42 in Alzheimerrsquos disease models and this blockageof neuroinflammation triggered by A120573 is involved in theneuroprotective effects of IndOH-LNCs It is a promisingapproach for treating AD [108]

55 Use of Chimeric Peptides However transport of thera-peutic peptides through BBB remains a challenge for peptidedrug delivery into the central nervous system (CNS) (Table 1)However chimeric peptides carry the drug into the brainto targeted sites though it does not transport through theBBB For this purpose drug is conjugated to a brain drug-targeting vector [109] These chimeric proteins easily passthrough BBB and presence of these peptide drugs inside cellcould be detected by immune-fluorescent markers Chimericprotein consists of a protein of interest covalently linked tonaturally fluorescent proteins that enable biologists to imagemovements of industrial proteins in living cells However byusing rDNA technology a chimera of any desired protein of

interest linked to a naturally fluorescent protein and expressinside a cell or an organism can be prepared

However tumor necrosis factor receptor-IgG fusionprotein is prepared for targeted drug delivery across thehuman blood brain barrier The tumor necrosis factor-alpha receptor (TNFR) contains an extracellular domain(ECD) that can be used in neurotherapeutics of stroke braininjury or chronic neurodegeneration [101 110] As nascentTNFR ECD is a large therapeutic molecule that does notcross the blood brain barrier (BBB) it was reengineeredby fusion of the receptor protein to the carboxyl terminusof the chimeric monoclonal antibody (mAb) to the humaninsulin receptor (HIR) This fusion makes it able to decoyreceptor transportable across the human BBB [110] Similarlymetabolically stable opioid peptide [3H]DALDA ([3H]Tyr-DArg-Phe-Lys-NH

2) was also prepared that is used as a

model drug which transports through the BBB into brainextracellular fluid [111] However cleavable disulfide linkersare used in the synthesis of such ldquochimeric peptidesrdquo Itis crucial to save S-S-bridge intact and stable during tran-scytosis However cleavage within endothelial cells couldresult in sequestration of the drug moiety instead of passagethrough the BBB [111] It was monobiotinylated with thecleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1 31015840-dithiopropionate (NHS-SS-biotin) to obtain bio-[3H]DALDA The biotinylated peptide is then bound to avector for brain delivery after intravenous injection in ratsa covalent conjugate of streptavidin and the transferrinreceptor monoclonal antibody OX26 Moreover the mostcommon strategy which is followed to treat moderate tosevere pain consists of the activation of opioid receptors inthe brain Hence the development of active opioid peptideanalogues as potential analgesics requires compounds witha high resistance to enzymatic degradation and an ability tocross the BBB

Moreover monoclonal antibody-glial-derived neuro-trophic factor a fusion protein penetrates the blood brainbarrier in the mouse Similarly majority of the fusionproteins are transcytosed across the BBB with penetrationinto brain parenchyma It was confirmed by brain capillarydepletion analysis [112] Similarly tetrapeptide analogues ofthe type H-Dmt1-Xxx2-Yyy3-Gly4-NH

2are transported into

the brain after intravenous and subcutaneous administrationand are able to activate the 120583- and 120575 opioid receptors moreefficiently and over longer periods of time than morphine[113] Similarly therapeutic elevations of GDNF could alsobe achieved in mouse brain with intravenous administrationof the cTfRMAb-GDNF fusion protein [112] Moreover abrain penetrating IgG-erythropoietin fusion protein wasconstructed which shows neuroprotective effects followingan intravenous treatment in Parkinsonrsquos disease in the mouse[114] Parkinsonrsquos disease (PD) is caused by oxidative stressand erythropoietin (EPO) reduces oxidative stress in thebrain However to make EPO cross the blood brain barrier(BBB) a brain penetrating form of human EPO has beendeveloped EPO is fused to a chimeric monoclonal antibody(MAb) against the mouse transferrin receptor (TfR) whichis designated as the cTfRMAb-EPO fusion protein TheTfRMAb acts as a molecular Trojan horse to transport the

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

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BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 11

fused EPO into brain via transport on the BBB TfR [114]Similarly avidin (AV) is fused to the carboxyl terminusof the heavy chain of the genetically engineered chimericmonoclonal antibody (mAb) against the mouse transferrinreceptor (TfR) The TfRMAb binds the endogenous TfR onthe blood brain barrier (BBB) which triggers transport intobrain from blood This cTfRMAb-AV fusion protein is anew drug delivery system that can target to mouse brainmonobiotinylated peptide or antisense radiopharmaceuticals[114] More specifically IgG-avidin fusion protein assists indelivery of a peptide radiopharmaceutical to brain [114]

Thus both recombinant fusion peptides and proteins areused as drugs which have shown great therapeutic efficacyagainst various neurodegenerative diseases But transport ofthese molecules (PP drugs) through blood brain barrier(BBB) is still a major challenge because of their larger size[115] Contrary to this smaller drugs have not been effectiveneuroprotective agents in either the acute treatment of strokesuch as focal brain ischemia or the chronic treatment ofneurodegeneration even after their larger permeability acrossBBB [93] More often large molecule drugs such as recom-binant neurotrophins and neurotrophins do not cross thebrain capillary endothelial wall but prove to be more effectivethan smaller size drugs Hence to make neurotrophinstransportable across the BBB chimeric peptides are made inwhich a neurotrophin is reformulated by fusion to a transportvector Transport vector is a peptide or peptidomimeticmonoclonal antibody that undergoes receptormediated tran-scytosis through the BBB and acts as amolecular Trojan horse[93] Similarly glial-derived neurotrophic factor (GDNF) is aneurotrophin that could be developed as a agent for treatmentof Parkinsonrsquos disease stroke and motor neuron disease[61] Therefore by reengineering of GDNF neurotrophinwas made transportable across the human BBB by fusion ofthe mature GDNF protein to the carboxyl terminus of thechimeric monoclonal antibody (MAb) to the human insulinreceptor (HIR) [61] However peptides or protein therapeu-tics may be delivered to the brain with the use of the chimericpeptide strategy However to make chimeric peptide strategysuccessful vector development and coupling of drugs tothe vector and liberation of biologically active peptidesfollowing cleavage of the bond linking are important steps[116] Furthermore avidinbiotin system is proved to bemoreadvantageous in fulfilling these criteria for successful linkerstrategies However OX26 monoclonal antibody are used inavidinbiotin system and a vasoactive intestinal peptide (VIP)analogue is fused to make it suitable for monobiotinylationand retention of biologic activity following cleavage [116] Inaddition in chimeric peptide delivery method proteins suchas cationized albumin or the OX26 monoclonal antibodyare used as transport vectors and bound to the transferrinreceptor These proteins undergo absorptive-mediated andreceptor mediated transcytosis through the BBB respectively(Table 1) [116]

Moreover endogenous peptide modified protein orpeptidomimetic monoclonal antibody (mab) that under-goes RMT (Rapid metabolic transfer) through the BBB onendogenous receptor systems such as the insulin receptoror the TfR is also used Interestingly this peptidomimetic

mabs bind to exofacial epitopes on the BBB receptor thatis removed from the endogenous ligand binding site andpiggyback across the BBB Drug is monobiotinylated andfused with a vectoravidin or a vectorstreptavidin (SA)fusion protein [109] Because of extremely high affinity ofavidin or SA binding of biotin there is instantaneous captureof the biotinylated neurotherapeutic agent made by thevectoravid in or vectorSA fusion protein [117] Furthermoremonoclonal antibodyavidin and mabSA fusion genes andfusion proteins are produced by using genetic engineeringmethods that are proved to be good delivery methods inhumans [118]

56 Disruption of BBB by Using Focused Ultrasound Forfast action of a drug its successful delivery in to the brainand its proper distribution is highly essential Furthermorefor safe and noninvasive distribution of drug reversibly attargeted locations needs disruption of blood brain barrier(BBB) This BBB disruption is induced by pulsed ultrasoundin the presence of preformed gas bubbles It is operated verycarefully because over pitch sound may harm brain tissuesTherefore sonication should be provided in a controlledmanner to make it noninvasive and reversible to deliver thedrug at targeted locations without inducing substantial vas-cular damage (Table 1) Because ultrasonic results in ischemicor apoptotic death to neurons [119] it has emerged as animportant diagnostic technology that is used for localized andreversible disruption of the BBB for treatment purposes [1]It has wider applications in molecular neurooncology [24]Similarly ultrasound induced MRI guided BBB disruptioncould also be possible for drug delivery into the brain [1]Similarly few other strategies are also in developing phaselike burst ultrasound which is performed in the presenceof an ultrasound contrast agent that also disrupts BBB byusing acoustic waves in the selected region of the brain HRPinjected in the brain passes through MRI induced BBB dis-ruption at pressure amplitude between 04MPa and 14MPa[120] Further EM that demonstrated HRP passage throughvessel walls via both transendothelial and paraendothelialroutes proves disruption It is a much safer method fortargeted drug delivery than any other convection methodemployed for drug delivery [120 121] Both of these tech-niques have emerged as noninvasive methods No doubt thatdiagnostic technology based on MR (magnetic resonance)imaging assists in monitoring of therapeutic agents theirdistribution and kinetics in neuronal tissues (Table 1) [122]

Some other strategies such as radiation therapy orchemotherapy are used for tumor therapeutics which donot provide good prognosis tumor progression control orimproved patient survival [122] Further temporal disruptionof the BBB by microbubble-enhanced focused ultrasound(FUS) exposure can increase CNS blood permeability pro-viding a promising new direction to increase the concen-tration of therapeutic agents in the brain to control tumorformation necrosis and tissue invasiveness It shows no longterm adverse effect and provides longevity in the patientsFurther for BBB break-down mannitol solution is injectedinto arteries in the neck that results in high uptake of sugar

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

hics

heetsr

olledin

tosin

gleo

rm

ultiw

alledtu

beslt

10nm

predict

emiss

ionfre

quen

cies

bright

eran

dsta

bles

igna

lint

ensit

yco

njug

atet

opr

oteins

fort

arge

ting

com

pose

dof

cyto

toxich

eavy

metals

unstab

lein

UV

radiation

Use

din

vitro

labe

lingof

liver

cells

fluo

rescen

tassay

sto

detect

antig

enso

nce

llsu

sedin

vivo

canc

erde

tection

anddiag

nosis

Mor

estables

igna

lsth

anflu

ores

cent

molec

ulesb

right

erc

anbind

with

proteins

Den

drim

ers

5ndash20

nmhi

ghly

bran

ched

mac

rom

olec

ules

synt

hesiz

edth

roug

hpo

lym

erizationreac

tion

grow

ingou

twardfro

mac

entral

core

5ndash10

bra

nche

dstr

uctu

reallowsh

ighdr

ugca

rriage

Caus

edos

eand

surfa

cech

arge

depe

nden

them

olys

iscy

totoxicinvitro

targe

tedde

liver

yof

drug

sin

aque

ouss

pace

with

inlip

osom

eori

nterca

lated

into

lipid

bilay

ers

used

inge

nede

liver

y

Show

polym

erization

term

inal

grou

psca

nbe

mod

ified

ford

rugtarg

etin

gsh

owhi

ghdr

ugca

rriage

Fulle

rene

s15

ndash500

0leng

than

d05ndash

20diam

eterv

erysim

ilart

oca

rbon

nano

tube

sanex

tend

ed120587

conjug

ated

carb

onsk

eletons

Vapo

rizationof

grap

hites

Heterof

ullerene

s13

Clabe

ledfu

llerene

saz

afullerens

Highe

rdru

gde

liver

yforb

rain

tum

ors

BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

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[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

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[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

12 BioMed Research International

by brain capillaries which also takes up water out of theendothelial cells shrinks them and opens tight junctionThis effect lasts for 20ndash30 minute during such time drugsdiffuse freely that would not normally cross the BBB Thismethod permitted the delivery of chemotherapeutic agentsin patients with cerebral lymphoma malignant glioma anddisseminated CNS germ cell tumors [117 123] In additiondisruption or damage of endothelium could allow expressionof endothelial receptors which are normally downregulatedopening new communication loops between endotheliumpericytes astrocytes and microglia These also play animportant role in barrier repair Physiological stress transientincrease in intracranial pressure and unwanted delivery ofanticancer agents to normal brain tissues are the undesiredside effects observed in man

57 Loaded Microbubble Enhanced Focused UltrasoundBesides the above methods blood brain barrier can betemporarily and locally opened by focused ultrasound in thepresence of circulating microbubbles [124] Microbubbles aresmall ldquobubblesrdquo of monolipids that are able to pass throughthe blood brain barrier They form a lipophilic bubble thatcan easily move through the barrier [119] The ultrasoundincreases the permeability of the blood brain barrier by caus-ing interference in the tight junctions in localized areas Thuscombined effect ofmicrobubbles and ultrasonic sound allowsdrug into a very specific area with the diffusion of microbub-bles More often microbubbles diffuse only where the ultra-sound disrupts the barrier Focused ultrasound is also usedto deliver targeted NK-92 cells to the brain using a model ofmetastatic breasts cancer [125] Thus loading a microbubblewith an active drug to diffuse through the barrier and targeta specific area increases the usefulness and action of drug[119] It was also found to be more feasible for targetedgene transfer into central nervous system by MRI guidedfocused ultrasound induced blood brain barrier disruption[126] Similarly doxorubicin-loadedmicrobubble technologyhas been developed that destroys tumors with focused ultra-sound and makes fragments Further nanoshards formed arecapable of escaping through the leaking tumor vasculaturepromoting accumulation of drug within the interstitium[127] Thus hydrophilic drug doxorubicin and paclitaxelloaded microbubbles are used for ultrasound triggered drugdelivery [127] Similarly hydrophobic drug paclitaxel loadedUCA (polymer ultrasound agents) triggered with focusedultrasound showed enormous potential for targeted andsustained delivery of drug to tumors [127] Instead ofmicrobubble size its route and stability must be deter-mined for delivering the drugs to specific sites in the brain(Table 1) [119]

Similarly for safer and efficient drug delivery NPs(nanoparticles) are used as one of themajor potential deliveryvehicles to carry drug and distribute it in various locationsin human body via different pathways Therefore strategieswhich could successfully transfer nanoparticle to brain maysignificantly improve the efficacy of neuroprotective drugsin brain stroke [128] and neurodegenerative disease [129]

These could also be used to release oxidative stress gener-ated after pathogenesis [130] though brain contains highoxygen metabolism but lacks an antioxidation protectionmechanism [130] However oxidative stress associated withgene expression analysis can provide efficient information forunderstanding neuroinflammation and neurodegenerationassociated with NPS [130] Thus dysfunction of blood brainbarrier (BBB) will assist in drug delivery and carry it tomajor targets of pathological sites [131] It also enhances drugconcentration and its therapeutic action assists in treatmentof CNS related diseases disabilities and disorders whichseem to be very difficult to treat [129] Further both receptorand site of action of drug at BBB require better drug designsthat could not only enhance its activity and selectivity butalsomake significant increase in the therapeutic index of drug[129] (Table 1)

Further the size of the drugmolecule seems to be amajordeterminant factor inCNS therapeuticsWhether a substanceabsorbs and comes across the nasal respiratory epitheliumandor transports along the olfactory pathway it needs aperfect smaller size [132] Other factors which affect thedrug delivery to the brain include the degree of dissociationsand lipophilicity However higher lipophilicity may resultin better transportation of therapeutic agents Once a drugis transferred in the brain it is further influenced by BBBefflux transporter systems like P-glycoprotein (P-gp) [133]Its uptake into the brain could be enhanced when drugs areadministered in combination with the P-gp efflux inhibitorrifampicin [48 134] Further there is no effective therapeuticintervention developed to check cerebrovascular toxicity ofdrugs of abuse such as methamphetamine [135] Similarlyto enhance antioxidant capacity of cerebral microvesselsintensive physical exercise could protect against METHinduced disruption of blood brain barrier [135] Howeverphospholipid enclosed vesicles released by both eukaryotesand prokaryotes into their environment remove harmfulmolecules by vesicle cargos These could be used to exchangebiomolecules by loading on transmembrane receptors Thesealso deliver genetic information by same route and samemechanism [136] These vesicles protect cell from accumu-lation of wastes and drugs inside the cell Microvesicleshave many chemical applications and are used as biomarkersin cancer therapy [136] These vesicles easily pass throughblood brain barrier and act like naturally occurring liposomesand endowed drugs may transfer to brain and persist fora longer period Thus drug persistence for longer durationprotects brain from virus infection injuries [136] cancerand certain epilepsies [137] Moreover equilibrium must beestablished between cerebrovascular permeability when adrug is transferred via the circulatory system for the therapyof neurodegenerative diseases However to avoid differentbarrier inhibiting CNS penetration by the therapeutic sub-stances various drug delivery methods such as chemicaldrug delivery and carrier mediated drug delivery have beenestablished [129]

Furthermore contrast enhancedmicrobubble ultrasoundis a noninvasive method which is used for assessment ofbreast lesions [138] These are detected prior to larger bub-bles following decompression [139] Gas microbubbles are

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 13

highly comprehensive but phospholipid coated microbub-bles generate large change in resonance frequency These areused for measurement of small blood pressure variationsin deep blood vessels [139] and absolute blood pressure insurface organs [139]However lipid shelledmicrobubbles andalbumin shelled microbubbles are used to deliver drug tobreast cancer cells [140] Similarly biotinylated microbubbles[141] and methylene microbubbles are used in dual modalityultrasound and activatable photoacoustic imaging [142] andin sonothrombolysis [143] Therefore ultrasound stimulateddrug delivery is done for treatment of residual disease[144] Similarly drug perfusion enhancement in tissues couldbe achieved by steady streaming induced by oscillatingmicrobubbles [145] Further enhanced delivery of micro-RNA mimics cardiomyocytes using ultrasound responsivemicrobubbles resurfaces hypertrophy in an in vitro model[146] However combination of bubble liposomes and highintensity focused ultrasound and microbubble guided drugdelivery [147] are used for tumor ablation [147 148] Thususe of ultrasound induced disruption and microbubblescould successfully transfer nanoparticle to brain that maysignificantly improve neuroprotective efficacy of drugs inbrain stroke [129] and neurodegenerative disease [130]

6 Drug Delivery Methods

61 Proline Rich Peptides as Delivery Vehicles Certain pro-line rich peptides which pass through blood brain barrierare used for treatment of cerebral infections [149] Bestexample is oncocin that after entering into brain 80 ofit is trapped in the endothelial cells while other peptidessuch as drosocin and apidaecin Api 137 reached into theparenchyma cells and were found stable in the plasma andbrain [149] Bryostatin a potent protein kinase c (PKC)activator showed brain therapeutic efficacy [150] Similarlydolichyl-P increases transendothelial transfer of Rhodamine123 (Rh 123) and Ab 42 from the apical compartment tothe basolateral compartment [14] Thus its accumulationin the brain exerts an important role in the depressionof p-gp at the BBB and promotes function of the pumpat the BBB in AD Similarly anthocyanins found in berryfruits are active phytochemicals which show reversion of agerelated cognitive impairment and protect against neurode-generative disorders [151] Hence this is more plausible thatmechanism of neuroprotective action of anthocyanin maybe via modulation of signal transduction processes andorgene expression in the brain tissue [151] Similarly CFC-C showed significant neuroprotective effect as it containedvarious components on apoptosis related proteins Howeverflavonoid and polysaccharide components in Jiawei WuziYanzong formula can pass through the blood brain barrierand protect neurons from beta amyloid protein inducedneurons up to some extent [138]

Similar neuronal protective efficacy is also observed inAstragali radix (AR) by oral administration against Japaneseencephalitis virus (JEV) infection in mice However in ARtreated mice peritoneal exudates cell (PEV) or macrophagenumbers get increased and active oxygen production was

obtained high [152] It shows a significant increase in survivalrates in animal groups with RA and this effect was found tobe dependent on a nonspecific mechanism during the earlyphase of infection [152] Similarly Quin Wen oral liquid pro-tects the experimental rabbits facing hemorrhagic fever [153]It delays the incubation period lowering down febrile indexand PGE context It improves hemorheology and enhancesthe cell mediated immunity in CSF [153] Similarly arginase 1has been shown to protect motor neurons from trophic factordeprivation It allows sensory neurons to overcome neuriteoutgrowth inhibition by myelin proteins Similarly daidzeinconsumed with soya products crosses the blood brain barrierand appears to be safe and effective without any pretreatmentIt can be developed as an ideal candidate for development oftherapeutic drugs for spinal cord injury or strike Similarlyglutamate antagonists were found to be highly useful andare used to protect neural tissues against Ischemia Theantagonists such as magnesium MK 801 and combinationof magnesium and MK 801 reduce brain edema and restoreBBB permeability after experimental diffuse injury [154]Similarly oximes are used to mitigate O induced neuronalinjury They restart or reactivate inhibited organophosphatelocal AChE [155] Similarly subfragments of amyloids betaappear to protect neurons from Alzheimerrsquos disease [156]Moreover Chitosan microspheres are used to trap the drugand form a nanocarrier for its permeation through the BBBIt is a novel method mostly used in nanovaccine delivery[157] It can be used to deliver drugs to treat virus infectiondementia [158] and neurocognitive disorders (Table 1) [159]This is also used to activate angiotensin converting enzyme(AE) inhibitors those which cross blood brain barrier [159]Similarly erythropoietin (EPO) also acts as a neuroprotectorthat is used through intranasal delivery [45 157] It is anoninvasive method which bypasses the blood brain barrier(BBB) in order to deliver therapeutic agents to brain [157]More specifically N acetylcysteine amide (NACA) protectsthe blood brain barrier (BBB) from oxidative stress inducingdamage in gp 120 Tat and methamphetamine treated animals[160] Thus it could become viable therapeutic option forpatients with HIV-1 associated dementia (HAD) [160] Inaddition antiretroviral treatment prevents central nervoussystem dysfunction by decreasing brain viral load and inter-feron alpha levels [159]

62 Nanoparticles as Drug Delivery Vehicles Nanoparticlesare nanoscale sized polymeric particles which are made upof natural or artificial polymers These are ranging in sizebetween about 10 and 1000 nm (1mm) These interact withbiological barriers and easily pass through it and are usedfor drug targeting and biodistribution of pharmaceuticalsin a controlled manner Drugs can bound in form of asolid solution or dispersion or adsorbed to the surface orchemically attached on nanoparticles support carrier load-ing (Figure 4) Further polymer used in construction ofnanoparticles improves their stability in the biological envi-ronment It also assist to mediate the biodistribution of activecompounds drug loading drug targeting transport releaseand interaction with biological barriers But in normal cases

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

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BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

14 BioMed Research International

Entrapped hydrophilic drugsLipid bilayer

Liposomes

Encapsulated drugNucleic acids

Nanocapsule

Nanosphere

Micelles

Entrapped drug

Lipophilic drugsHydrophilic headHydrophilic tail

Conjugated drugTargeting moiety or imaging agentDrug molecule

Nanoconjugate and linear polymers

Dendrimer

(a)

Nanoparticle Drug loaded nanoparticle

(b)

Figure 4 (a) Showing structures of different types of drug delivery vehicles (b) a drug loaded nanoparticle

use of nanopolymers is proved to be invasive and toxic astheir degradation products create serious problems in theCNS However cytotoxicity generated by nanoparticles ortheir degradation products remain a major problem in drugdevelopment However valid improvements in biocompati-bility are much needed hence it should be the main concernof future pharmaceutical research [161]

Nanoparticles have enormous medical applications andemerged as the major tools in nanomedicine than conven-tional drug delivery methods [162] These provide massiveadvantages regarding drug targeting delivery and releaseFurther their additional potential can be harnessed to com-bine diagnosis and therapy which will work as much usableemerging tools in nanomedicine [163]These are proved to bebest delivery vehicles to carry drugs to biological systems fora safer therapeutics of variety of neurodegenerative and virusgenerated diseases These are highly efficient drug deliverysystems that are potentially used for many applicationsmainly in antitumors therapy gene therapy AIDS therapyand radiotherapyThese are also used for delivery of proteinsantibiotics virostatics and vaccines and are used as carriersor vesicles to pass the blood brain barrier [162 163] Inaddition these drug delivery systems have potential usein transfer of molecular and immunological agents to thebiological system These are used for gene delivery andto make recombinant therapeutic peptides synthesized by

fusion of new genes into the cells It can ably transfer neu-rotrophic agents to abolish neurodegenerative diseasesThusnanoparticle permeation allows safe and sustained release ofdrug at the targeted site after 1 or 2 weeks of injection [164]More specifically nanoparticles have wider application inbrain tumor therapy and treatment of cancer and Alzheimerrsquosdisease [165]

There are twomain categories of nanoparticles inorganicand organic These are mentioned in Table 2 Inorganicnanoparticles are mainly magnetic metallic nanoshells andceramic Magnetic nanoparticles are super paramagneticiron oxide particles that display large magnetic moments ina magnetic field These are biocompetitive noncompatiblechemically stable and easy to manufacture These are mostlyused for targeted delivery of drugsgenes and are used inthermotherapy Next category of nanoparticles is metallicnanoparticle which comprises gold or silver or copper andiron nanoparticlesThese are smaller in size (lt50 nm) havinglarge surface area carry high drug doses but these showpoor biocompatibility and have no decided function whenused in vivo These are used for controlled release of drugsproteins and DNA encapsulated in hollow cores of metalshells at desired sites These are widely used in catalysissensing imaging and drug delivery Silica nanoparticles arenanoshells that possess similar imagingtherapeutic potentialas quantam These are less toxic and are relatively large in

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

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BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 15

Tabl

e2

Diff

eren

ttyp

esof

inor

gani

cnan

opar

ticles

theiru

ses

andap

plicationin

biom

edicin

e

Inor

gani

cnan

opar

ticles

Com

posit

ion

Applications

Adva

ntag

esCh

itosa

n-na

noco

njug

ated

horm

onen

anop

artic

les

Chito

sanan

dho

rmon

eDeli

vern

ontoxic

polynu

cleot

idep

harm

aceu

ticals

tone

uroc

ompa

rtm

ents

Show

low

imm

unog

enicity

Insu

linna

nopa

rticles

Polym

eric

nano

particle-cro

ss-li

nked

bea

dsOra

ldeliver

yof

insu

linim

itatest

hepr

oduc

tion

ofin

sulin

bypa

ncreatic

islet

cells

Ove

rcom

ecan

cerd

rugresis

tanc

etarg

eted

treatm

enta

cros

sbar

rier

Smrh

opr

oteinload

edch

itosa

nCoa

tedwith

sodium

algina

teor

algina

teOra

lvac

cina

tion

stablea

ndfin

etarge

tac

cessibilitya

ndgo

odim

mun

izationag

ains

tSman

soni

Great

stabilit

yan

dea

seof

targ

etac

cessibility

imm

unos

timulator

y

Chito

san-

sodium

laur

ylsu

lfate

nano

particles

Ani

onic

surfa

ctan

tsod

ium

laury

lsulfate

Ora

ldeliver

yof

insu

linb

iode

grad

able

stab

lein

simulated

gastric

fluids

andbioa

vaila

bilit

yIm

prov

eins

ulin

oral

bioa

vaila

bilit

y

Chito

san-

Plur

onic

nano

particles

Chito

sanan

dPl

uron

icF-

127

Efficien

tora

lfor

mulationforc

olon

canc

ertre

atm

ent

Effec

tived

eliver

ysy

stem

with

few

sidee

ffects

Chito

san-

DNA

nano

particles

Aco

mplex

coac

erva

tionof

DNAc

hito

san

and

sodium

sulfa

tePr

otec

tthe

enca

psulated

plas

mid

andin

crea

setran

sfectioneffi

cien

cyBe

tterl

oading

rele

ase

andce

llup

take

Lecith

inchito

sanna

nopa

rticles

Chito

sanan

dlecith

inco

lloidal

susp

ensio

nPr

ogestero

nede

liver

ym

odel

lipop

hilic

drug

and

show

sgoo

den

caps

ulationeffi

cien

cies

Tran

sder

mal

deliv

eryof

melaton

inb

ioco

mpa

tible

Chito

san-

coated

ironox

ide

nano

particles

Fe3O

4na

nopa

rticlesa

scor

esan

dch

itosa

n(C

S)Non

cytotoxic

PEG-C

S-Fe

3O4as

astable

mag

netic

targ

etin

gdr

ugca

rrieri

nca

ncer

therap

yAnt

ican

cere

ffect

agains

thum

anov

arianca

ncer

cells

targe

tint

egrin

richtu

mor

cells

FVIII-ch

itosa

nna

nopa

rticles

DNA

polyplex

esco

mpo

sedof

chito

san

andfactor

VIIID

NA

Ora

ldeli

very

ofan

onvira

lgen

ecar

rier

hem

ophi

liaA

gene

therap

y

Non

vira

ldeliver

yforg

enem

edicin

eapp

lications

de

liver

ysy

stem

prac

tical

forh

emop

hilia

Age

neth

erap

y

PEGylated

chito

san-

mod

ified

Lipid-

base

dpo

ly(eth

ylen

eglyco

l)(P

EG)

Non

toxicb

iode

grad

able

orala

ndde

rmal

applications

im

prov

ethe

efficien

cyof

thed

rug

PEGylated

chito

sanpr

olon

gedth

ereten

tiontim

eof

then

anop

artic

lesi

nth

ecirc

ulator

ysy

stem

and

impr

oved

theb

ioav

ailabilit

yof

cyclo

spor

inA

mPE

G-P

LACy

closp

orin

A-load

ed

Polym

eric

micelles

base

don

mon

ometho

xypo

ly(eth

ylen

eglyco

l)-b-

poly(d

l-lactic

acid)

(mPE

G-P

LA)

Spatiald

istrib

utionof

thed

rugwith

inth

ena

nopa

rticles

Impr

ovet

heor

albioa

vaila

bilit

yof

poor

imm

une

resp

onse

mPE

G-P

LACy

closp

orin

A-load

edW

ater

solublec

yclosp

orin

A(C

yA)a

ffected

the

intestin

alP-

gpeffl

uxpu

mps

Goo

dca

ndidatef

oror

alde

liver

yof

poor

lyso

luble

drug

sStab

lean

dm

onod

isperse

nano

particles(

NPs

)in

aque

ouss

uspe

nsion

Chito

sanPG

Ana

nopa

rticles

(PLG

ANP)

Polylactic-co-

glyc

olic

acid

inco

rpor

ated

nano

particles

Capa

city

inrepa

iring

andrege

neratin

gwou

nded

anddy

sfunc

tiona

ltiss

ues

Targ

eted

highlyeff

ectiv

eand

safe

treatm

ento

flung

canc

er

Thiolat

edch

itosa

nna

nopa

rticles

Aco

reof

polym

ethy

lmetha

crylate

surrou

nded

byat

hiolated

chito

san

Long

erha

lf-lif

eor

aldr

ugde

liver

ysy

stem

for

antic

ance

rdru

gsPo

tent

iale

nhan

cerb

ucca

ldeliver

yof

insu

lin

tens

ilestr

ength

andbioa

dhesionforce

Beta

cyclo

dextrin

carries

Am

mon

ium

beta

cyclo

dextrin

(C

h-GSH

-pM

MA)

Ant

ican

cerd

rugde

liver

yve

hicle

sBi

ocom

patib

leless

toxic

Qua

tern

aryam

mon

ium

120573-cyc

lode

xtrin

(QA120573CD

)Am

mon

ium120573-cyc

lode

xtrin

Carrierf

ordo

xoru

bicin(D

OX)

and

hydr

opho

bic

antic

ance

rdru

gac

ross

theB

BBGreat

potent

ialinsa

fely

andeff

ectiv

elyde

liver

ing

DOX

andot

hert

herape

utic

agen

tsac

ross

theB

BB

120573-C

yclode

xtrin

inclu

sion

com

plex

es120573-C

yclode

xtrin

(120573-C

D)

enca

psulation

Deli

very

ofne

urop

rotectived

rug

Form

inclu

sionco

mplex

eswhi

charea

prom

ising

form

ulationform

elan

omat

reatm

ent

tran

sder

mal

deliv

eryof

drug

s

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

16 BioMed Research International

Tabl

e2

Con

tinue

dIn

orga

nicn

anop

artic

les

Com

posit

ion

Applications

Adva

ntag

es

Am

oxicillin120573-cyc

lode

xtrin

Am

oxicillin

and120573-la

ctam

cyclo

dextrin

sof

diffe

rent

sizes

Low

toxicity

andlow

phar

mac

olog

ical

activ

ity

protec

tdru

gm

olec

ules

from

biod

egra

datio

nin

crea

seddr

ugtran

spor

t

Ora

llyad

min

istered

sustaine

dreleas

efor

mulation

fort

hetre

atm

ento

fpep

ticulce

rs

PLGA

nano

particles

poly(la

ctide-co

-glyco

lide)

Poly(la

ctide-co

-glyco

lide)(P

LGA)

abiod

egra

dablep

olye

ster

Ant

ican

cere

nhan

ceddr

ugde

liver

yto

tum

orce

lls

high

ereffi

cacy

and

fewer

sidee

ffects

Ant

ibod

yco

njug

ated

ICG-D

OX-

PLGA

nano

particlesh

avep

oten

tialfor

com

bina

toria

lch

emot

herapy

andhy

perthe

rmia

Lans

opra

zole-lo

aded

nano

particles

Lans

opra

zole-lo

aded

Eudr

agitRS

100

nano

particles(

ERSN

P-LP

Z)as

well

aspo

ly(la

ctic-co-

glyc

olic

acid)

Susta

ined

andpr

olon

geddr

ugde

liver

yNov

ellans

opra

zole-lo

aded

nano

particlesf

orth

etre

atm

ento

fgas

tric

ccid

secretion-

relat

edulce

rs

Nan

ocry

stals

Agg

rega

teso

fmolec

ulesc

rystallin

efor

mof

drug

Bette

rbiologica

ldist

ribut

ionan

dbioa

vaila

bilit

yRe

duce

toxice

ffect

ofdr

ug

Mag

netic

nano

particles

Supe

rpar

amag

netic

ironox

idep

artic

lesd

isplay

larg

emag

netic

mom

ents

inam

agne

ticfie

ldTa

rgetin

gtu

mor

cells

Indu

ctionof

matur

ationon

dend

ritic

cells

via

NF-120581B

signa

lingpa

thway

Iron

oxiden

anop

artic

les

Ferrom

agne

ticiro

nox

iden

anop

artic

lesan

dm

aghe

mite

(y-F

e 2O

3)an

dm

agne

tite(

Fe3O

4)na

nopa

rticles

Sono

chem

ical

deco

mpo

sitionof

iron

pent

acar

bony

ltarg

etintegr

inric

htu

mor

cells

Insituform

inghy

brid

ironox

ide-hy

alur

onic

acid

hydr

ogel

form

agne

ticreso

nanc

eim

agin

gan

ddr

ugde

liver

yMetallic

Silver

nano

particles

Ag+ -

NOM

-Iro

n(IIIII)s

ystem

sAnt

ibac

teria

lactivity

cont

rolle

dreleas

eofd

rugs

pr

oteins

and

DNA

Silver

nano

particlesc

rossin

gth

roug

han

ddistr

ibut

ionin

theb

lood

brainba

rrierinvitro

gliom

atreatm

ent

Goldna

nopa

rticles

Goldso

lidna

nopa

rticles

Goo

dbioc

ompa

tibility

andea

sysu

rface

mod

ifica

tionut

ilize

theG

NPs

asm

ultif

unctiona

lpr

obes

tum

ormdash

spec

ifict

arge

tingm

oieties

cont

rolle

dreleas

eofd

rugs

pro

tein

san

dDNA

andus

edin

photoa

cous

tictom

ograph

y

Enca

psulation

bios

ensin

gan

dim

agin

gwhe

nde

coratedwith

oligo(

ethy

lene

glyc

ol)t

hiolss

how

increa

sein

surfa

cech

arge

sand

intera

ctions

with

proteins

inso

lutio

n

Nanoshells

Silic

anan

opar

ticles

Coe

xiste

nceo

fhyd

roph

ilics

urface

silan

ol(ndash

SindashO

H)a

ndde

proton

ated

silan

ol(ndash

SindashO

ndash)gr

oups

photos

table

Non

toxicity

andgo

odbioc

ompa

tibility

prep

ared

byso

l-gel

metho

d3-

amin

opro

pyltr

imetho

xysil

ane

allyltr

imetho

xysil

ane

Easil

ycros

sthe

bloo

dbr

ainba

rriersh

owhigh

erdr

ugde

liver

yan

dsh

owtran

sferrin

gco

njug

ation

Ceramicnanoparticles

Laye

reddo

uble

hydr

oxide

nano

particles

Cop

recipitatio

nof

mixed

salts

40ndash

300n

m

Low

cytotoxicityb

ioco

mpa

tibility

Deli

very

ofan

tican

cerd

rugin

corp

orated

indo

uble

layere

nhan

cedan

tican

cert

herape

utic

effica

cyCa

lcium

phos

phate

nano

particles

Hyd

roxy

apatite

Exce

llent

bioc

ompa

tibilitylim

itedag

greg

ation

Bioc

ompa

tible

less

toxic

Polyso

rbate-co

ated

nano

particles

Polyso

rbate

Tran

spor

tedac

ross

thec

apillar

ywallim

prov

ethe

actio

nof

drug

oran

yot

herp

harm

aceu

tical

acro

ssth

ebar

rier

Mim

iclow-d

ensit

ylip

opro

tein

(LDL)

enh

ance

drug

deliv

ery

ATPbind

ingca

ssettes

Proteins

Protec

taga

inst

neur

otox

ican

tsan

dlim

itdr

ugde

liver

yredu

cexe

nobiot

iceffl

uxr

apid

tran

spor

tatio

nof

drug

acro

ssth

ecellm

embr

ane

neur

opro

tectivea

gent

Cereb

ralc

learan

ceof

endo

geno

usne

urot

oxic

com

poun

ds

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

edru

gca

rriers

Clos

edsp

heric

alas

sem

blieso

famph

iphi

licde

liver

yve

hicle

s10ndash

700n

m

Fort

herape

utic

agen

tsdr

ugsm

inim

izes

ystem

icex

posu

reg

enet

rans

ferv

ectoran

dm

odeo

fdeliver

ybioc

ompa

tible

andbiod

egra

dablem

ater

ials

applications

inbiom

edicin

eand

food

indu

stry

lip

osom

esca

nin

crea

seth

edru

gdistrib

ution

bioa

vaila

bilit

yan

dits

targ

eted

actio

nan

tican

cerd

rugs

Non

toxicb

iode

grad

able

prolon

gcirculationof

drug

s

Mag

neto

-lipo

som

esph

osph

olipid

bilaye

rs

50ndash1

00no

ntox

icbiod

egra

dable

nona

ntigen

iclow

syste

mic

toxicityp

rolong

circulationof

drug

sco

ntro

lled

Dru

greleas

ecau

seps

eudo

allerg

icin

flam

mation

cont

rolle

dde

liver

yof

drug

sinaq

ueou

sspa

cewith

inlip

osom

eintercalated

into

lipid

bilaye

rsg

ened

elive

ry

Non

toxicb

iode

grad

able

low

syste

matic

toxicityc

ontro

lleddr

ugreleas

e

Micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliq

uidco

lloidm

icellars

truc

turesm

ainlyco

reof

bloc

kco

polym

er

Micellesp

hysic

ally

entrap

pedth

edru

gan

dtran

spor

tit

toth

etarge

tareaa

ndreleas

ereq

uiredco

ncen

trations

form

edby

twofatty

acyl

chains

Deli

verl

arge

amou

ntof

drug

stoca

ncer

cells

Polym

eric

micelles

Anag

greg

ateo

fsur

factan

tmolec

ules

disp

erse

din

aliquidco

lloid10ndash

800n

m

New

drug

carriers

ystem

sstabilit

yin

plas

ma

long

evity

can

cerc

hem

othe

rapy

obstru

cttu

mor

angiog

enesis

Potent

ialtarge

tsof

antic

ance

rdru

gs

Carb

onna

notu

bes

Cylin

drical

grap

hite

shee

ts15

ndash500

0leng

than

d05ndash

20diam

etertrave

rsec

ellm

embr

anea

snan

onee

dles

ther

mal

Con

ductivity

targe

ttum

ors

Inso

lublei

naq

ueou

sm

ediac

ytotox

icp

oori

ncor

poratio

nca

pacitytarge

ted

deliv

eryof

drug

sge

nes

vacc

inesa

ntibod

ies

and

ther

mot

herapy

oftu

mor

s

Trav

erse

cellm

embr

ane

show

therm

alco

nduc

tivity

and

targ

ettu

mor

s

Qua

ntam

dots

Colloidal

grap

hics

heetsr

olledin

tosin

gleo

rm

ultiw

alledtu

beslt

10nm

predict

emiss

ionfre

quen

cies

bright

eran

dsta

bles

igna

lint

ensit

yco

njug

atet

opr

oteins

fort

arge

ting

com

pose

dof

cyto

toxich

eavy

metals

unstab

lein

UV

radiation

Use

din

vitro

labe

lingof

liver

cells

fluo

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

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[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 17

size compared with quantam dots These are used for pho-tothermal tumor ablation These form immunoconjugateswhich are highly applicable for immunoglobulin bioassayCeramic nanoparticles are made up of nonmetallic materialsthat are cheap and stable These can be formed by inorganicbiocompatible materials silica titania and alumina Theseare of smaller size (lt100) These are relatively flexible easy tomanufacture water soluble and biologically stableThese canform coatings and make bulk materials at low temperatures

Many types of organic nanoparticles such as carbonnanotubes quantam dots (semiconductors) dendrimersliposomes and polymeric nanoparticles have been made(Table 3) These are crystalline form of pure carbon Carbonnanotubes are graphite sheets rolled into single or multi-walled tubes Carbon nanotubes are used in electromagneticshielding of polymers composite for hydrogen storage andits batteries These are used for targeted delivery of drugsgenes and vaccines and are widely used in thermotherapy oftumors Quantam dots are semiconductor crystals formed bycombination of chemical elements from groups II III andV of the periodic table These are made up of cadmium coreand metal shell and have similar size lt10 nm These are usedin vitro labeling of live cells and for gene expression studiesfluorescent imaging assays to detect antigens or cells Theseare used for in vivo cancer diagnosis Dendrimers are highlybranched macromolecules synthesized through polymeriza-tion reactions These are used for targeted delivery of genesproteins and peptides Liposomes are closed spherical assem-blies of amphipathic phospholipid bilayerThese are nontoxicbiodegradable and nonantigenic in nature These are usedfor controlled release of drugs packed within liposomes orintercalated into lipid bilayers Polymeric nanoparticles arecolloidal nanoparticles which are made up of biodegradablepolymer matrices These are used for delivery of plasmidDNA proteins peptides and low molecular weight com-pounds These are mostly used to deliver water insolubledrugs (Table 3) Lipid-based polymer based and surfactantbased carrier systems have been developed for topical andtransdermal drug delivery (Figure 5) Other modificationsof liposomes such as PEGylated liposomes niosomes andaquasomes are also used for targeted drug delivery (Figure 6)

However different nanoscale carrier systems have beenmade by using number of materials such as poly(alkylcy-anoacrylates) (pacas) polyacetates polysaccharides andcopolymers for an easy and efficient drug delivery Four dif-ferent types of nanoparticles are constructed these are coatednanoparticles PEGylated nanoparticles solid lipid nano-particles and nanogels Mostly polyalkyl poly(alkylcy-anoacrylates) polyacetate polysaccharides and copolymersare used in construction of nanoparticles and for mak-ing efficient drug delivery system Nanoparticles made ofbiodegradable polymers such as polylactic acid polycapro-lactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydride chitosan and modified chitosan as wellas solid lipids have shown great potential in the delivery ofproteinspeptidal drugs However poly(butyl cyanoacrylate)nanoparticles are used for in vivo drug delivery to the brainsuccessfully In some cases it is reported to mimic moleculesthat would normally be transported to brain For example

polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL) allowing them to be transportedacross the capillary wall and into the brain by loading onthe LDL receptor [166 167] Further size and constructionmaterial not only increased their efficacy but also improvedthe action of drug or any other pharmaceutical agent acrossthe barrier [162 163 167] It allows sustained drug releaseat the targeted site after injection over a period of days orevenweeks [164] In addition newhydrogels and transdermaldrug delivery systems are to be developed for peptidal drugdelivery [168] The first drug that was delivered to thebrain using nanoparticles was the hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg) a Leu-enkephalin analogue withopioid activity

Nanoparticle based delivery methods are proved to bethe best methods to transfer drugs across CNS [12] Thesestrategies require multifunction NPs combining controlledpassage across the BBB These are proved to be the bestmethods to facilitate the delivery of drugs and biologicaltherapeutics for brain tumors across the BBB [12] Nanoparti-cles could easily traverse the BBB and carry drug to targetedlocations inside brain and tumor A better example is HAS(human serum albumin) that is used as nanoparticle Itis well tolerated to the patients and shows no serious sideeffect More exceptionally albumin functional groups can beutilized for surfacemodification of barrier that allows specificcell uptake [165] It also acts like as a transforming growthfactor in microbubble based drug delivery [166] Further toenhance the effectiveness of nanoparticles these are coatedwith certain biodegradable materials which make themmorepermeable to cross the blood brain barrier However lipidshelled and nonlipid shelled nanoparticles are prepared[169ndash171] Similarly biodegradable polymeric nanoparticles[172] transferrin-conjugated fluorescein-loaded magneticnanoparticles [173] solid lipid nanoparticles [169] and chi-tosan based nanoparticles [174] were made for targeteddelivery of drugs across the blood brain barrier Similarlyhydrogel-based ionotropic delivery devices are also devel-oped for transdermal delivery of peptideprotein drugs [175]Still it is a challenging task for nanotechnology in deliveryof imaging preface in biological systems [176] However toimprove the drug release and its biodistribution and forenhancing the therapeutic applications and efficacy esterprodrugs are incorporated into the nanoparticles [171] Theseare also coated with different hydrophilic or hydrophobicdrug materials [177] Mostly polysorbate-coated nanoparti-cles are used to deliver drug to the brain as these showed bet-ter efficacy than uncoated nanoparticle [177] Furthermorenanolipid carriers and solid lipid nanoparticles are used ascolloidal drug carriers for different therapeutics [178]

Because of their smaller size nanoparticles penetrate intoeven small capillaries and are taken up within cells Thusafter delivery an efficient drug accumulation takes place attargeted sites in the body [167] However to enhance thetherapeutic action of drug its maximum absorption in thetissues and organs is required Though exact mechanismof nanoparticle transport into brain is not understood itis thought to depend on the particles size material com-position structure and design of nanoparticles In some

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

ance

rthe

rapy

an

ti-vira

lage

nts

braintu

mor

s

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

din

maligna

ntm

elan

omas

andca

ncer

therap

ySu

ppress

effec

tsof

onco

gene

seffe

ctive

vehi

clesf

orde

liver

yof

PrP

Colloidal

drug

carriers

10ndash4

00nm

diam

etersi

nsiz

emicro

emulsio

nsCa

rgoca

rriers

inva

ccin

ethe

rapies

ofCN

Spa

thog

ens

Highdr

ugen

trap

men

tefficien

cyan

dload

ingca

pacity

Lipo

som

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

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[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

18 BioMed Research InternationalTa

ble3

Diff

eren

ttyp

esof

orga

nicn

anop

artic

les

theiru

ses

andap

plicationin

biom

edicin

e

Org

anic

nano

particles

Com

posit

ion

Applications

Adva

ntag

es

Pept

ide-ba

sed

nano

particles

Ferriti

npr

oteinca

gena

nopa

rticlesf

amily

ofpr

oteins

10

ndash500

nm

Chem

ically

orge

netic

ally

mod

ified

multif

unctiona

lpr

obes

fort

umor

imag

ing

ferriti

nis

pHde

pend

ent

nano

particles(

NPs

)dec

orated

with

tran

sferrin

(Tf)

Usedforn

asop

hary

ngea

lcan

cer-sp

ecifi

cth

erap

y

Lipid-

base

dna

nopa

rticle

Cholestero

lmed

iatedca

tioni

csolid

nano

particles

10ndash4

00nm

Use

dford

elive

ryof

proteins

andpe

ptides

andus

edfor

imm

une-stim

ulator

yRN

Aad

juva

ntc

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ti-vira

lage

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braintu

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Highdr

ugen

trap

men

tefficien

cyan

dload

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pacity

Solid

lipid

nano

particles

Colloidal

10ndash7

00nm

Solid

lipid

nano

particlesc

anbe

used

asco

lloidal

drug

carriers

forv

arious

therap

eutic

sph

arm

aceu

tical

altern

ativeo

flipos

omes

andem

ulsio

ns

Use

dto

deliv

erdr

ugor

ally

topica

llyo

rby

inha

latio

n

SiRN

Ade

liver

ysy

stem

sSiRN

A5ndash

40nm

Use

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BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

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[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 19

Carrier based topical and transdermal drug delivery systems

Lipid based systemsVesicle based

LiposomesDeformable Ethosomes

Particle basedSolid lipid nanoparticles

Nonstructured liposomesSolid lipid microparticles

Polymer based systems Biodegradable particles

Nonbiodegradable particlesDendrimers

Surfactant based systemVesicle based

NiosomesProniosomes

MicellesEmulsion basedMicroemulsionsNanoemulsions

Figure 5 Showing topical and transdermal drug delivery systems

NanoparticlesNanoemulsion Phytosomes

Microemulsion

Lipid particulate DDS

CubosomesIscorns

Virosomes Niosomes

Lipospheres

Ethosomes

Nanomers

Cochleates

LiposomesTransformers

Nanomicelles

Proniosomes

Figure 6 Showing different types of liposomes used for drug delivery to CNS

cases it is reported to mimic molecules that would normallybe transported to brain Further for targeting cancerousbrain tumors Photofrin is used along with iron oxide intonanoparticles Photofrin is a type of photodynamic therapy(PDT) in which the drug is drawn through the bloodstream to tumors cells Further a special type of laser lightactivates the drug to attack the tumor Iron oxide is a contrastagent that is used to enhance magnetic resonance imaging(MRI) Therefore nanoparticle based strategies have beendeveloped to establish equilibrium between cerebrovascularpermeability outside and inside of nerve cells

63 Chitosan Based Nanoparticles Chitosan based nanopar-ticles (NPs) require suitable drug carrier which could deliverthe pharmaceuticals to the various parts of neurocompart-ments [179] Interestingly chitosan NPs easily enter neuronal

cells by endocytosis and transfer through membrane boundvesicles and free in the cytosol and accumulate aroundthe nucleus [179] However for sustained surge of certainhormones chitosan-nanoconjugated hormone nanoparticles[180] such as insulin nanoparticles are prepared for oral deliv-ery [181] Similarly Smrho protein loaded chitosan nanopar-ticles [182] and chitosan-sodium lauryl sulfate nanoparticles[183] are also prepared for oral delivery of insulin andother therapeutic agents [182 184] In addition chitosan-Pluronic nanoparticles are used as oral delivery of anticancergemcitabine [185] Similarly low molecular weight chitosannanoparticulate system at low N P ratio are also preparedfor nontoxic polynucleotide delivery [186] Further differenttypes of nanoparticles such as chitosan-DNA nanoparticles[187] lecithinchitosan nanoparticles [188] chitosan-alginate[189] and chitosan-coated iron oxide nanoparticles are also

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

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[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

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[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

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[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

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[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

20 BioMed Research International

prepared for sustainable drug delivery [190] Moreover 5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer are used in pho-todynamic therapy [191] while FVIII-chitosan nanopar-ticles [192] cyclosporin A-loaded PEGylated chitosan-modified lipid-based nanoparticles [193 194] and chitosanand poly(lactic-co-glycolic acid) incorporated nanoparticles(heparin) are also prepared for quick CNS therapeutics [195]Similarly thiolated chitosan nanoparticles are also preparedfor drug delivery system for antisense therapy [196] (Table 2)

Further for improving the therapeutic and pharmaco-logical efficacy of drugs its natural structure is protectedby encapsulation It makes the drug able to cross biologicalbarriers and carry it to intracellular target sites [179] Besidesthis brain penetration may enable the drugs in controlledstate that will minimize the overdose effect and accessibilityof drug candidate into the CNS compartment [197] Fur-ther required accumulation of drug needs appropriate andprospective drug design based on normal delivery principlesto save the CNS from xenobiotic substances or its adverseeffects [197] Therefore in new therapeutics nanoparticlesallow sustained release of drug into brain critically neededfor treatment of CNS related diseases (Figure 2) [198] Itcan ably transfer neurotrophic agents for curing many neu-rodegenerative diseases of central nervous system (CNS) Inaddition for treatment of neurological disorders novel drugcandidate should be identified [199] and more approachabledrug design with higher drug action and its possible effects inbrain tissues are enumerated [197] In addition nanoparticlebased gene delivery vehicles could transfer genes to restoreneurodegenerative disease like Alzheimerrsquos Parkinsonrsquos andEpilepsy and brain tumors Further nanoparticle generatedcytotoxicity should be evaluated in animal models like Zebrafish [200]

64 Beta-Cyclodextrin Carriers Similarly ammonium beta-cyclodextrin (QA beta CD) nanoparticles are used as drugdelivery vehiclescarriers for doxorubicin (Dox) a hydropho-bic anticancer drug across the blood brain barrier (BBB)(Figure 5 Table 2) [201] Bcrp (barrier cancer resistanceprotein) a major component of the blood brain barrier islocated on endothelial cells near the tight junctions [202]It lacks in Sertoli cells and is known as blood testis barrier(BTB) instead it is localized to the endothelial tight junctionin microvessels in interstitium and peritubular myeloid cellsin the tunica propria [202] Bcrp is an ATP dependentefflux transporter [202] Similarly l-arginine in inclusioncomplexes of omeprazole with cyclodextrins [203] makes ahydrophobic pharmaceutical mediated self-assembly of 120573-cyclodextrin containing hydrophilic copolymers It is used asnanovehicles for neuroactive drug delivery (Table 2) [204]Many cyclodextrin based nanoparticles have been preparedwhich show different physicochemical properties and dis-solution Further cyclodextrin based nanosponges havebeen made for delivery of resveratrol [205] In additionfew important 120573-cyclodextrin inclusion complexes are pre-pared by using dexamethasone acetate-120573-cyclodextrin [206]amoxicillin 120573-cyclodextrin [207] ethyl cellulose-coated

amoxicillinchitosan-cyclodextrin-Based Tablets [208] andpiroxicam-120573-cyclodextrin [209] Further improvement indissolution behavior of poorly water soluble drug was doneby using cyclodextrin in extrusion process [210] Similarlyinclusion complex of novel curcumin analogue CDF and120573-cyclodextrin was prepared to enhance in vivo anticanceractivity against pancreatic cancer [211] Similarly sulfobutylether 120573-cyclodextrin (SBE

7120573-CD) carbamazepine complex

was prepared that showed in vivo antiepileptic activity [212]Moreover mechanism of addingremoving acetyl groups tohistone lysine residues is one of many epigenetic regulatoryprocesses which control the expression of genes many ofthem are essentially required for neuronal survival [213]

65 ATP Binding Cassettes TheATPbinding cassettes (ABC)transporters are important selective elements of the bloodbrain barrier (Table 2) These occur over the laminal plasmamembrane of the brain capillary endothelium facing thevascular space [214] and protect against toxic effects bylimiting drug delivery to the brain [170] These selectivelybind to neurotoxicants and prevent entry of neurotoxicantsby limiting their accessibility into brain parenchyma [214]These operate throughmultiple signaling pathways followingof expression and activity of P-glycoprotein ABC trans-porters are modulated in response to xenobiotics stress anddisease [214] Further deficiency of P-glycoprotein at the BBBinhibits the efflux activity of certain biomolecules at the bloodbrain barrier which also protect the brain from overdose[14] However increased transporter expression occurs inresponse to signals that activate specific transcription factorsincluding pregnane a receptor constitutive androstane recep-tor nuclear factor kappa beta and activator protein 1 [214]

ABC transporter proteins with the aid of energy derivedfrom ATP hydrolysis are used to export a large varietyof drugs from the cytosol to extracellular medium ABCtransporter proteins are expressed inmany different cell typesfrom different organs but exceptionally these are expressedin luminal cells and multidrug resistant transport proteins incase of tumor and cancer cells Further expression of ATPdriven efflux transporters in barriers and excretory tissues isregulated by certain ligand activated nuclear receptors [170]Similarly Mrp 2 multidrug resistance associated protein 2and breast cancer resistance protein (BcRP) and CAR aredetected and expressed in rat and mouse brain capillaries[170]Moreover CARactivation selectively tightens the bloodbrain barrier by increasing transporter activity and proteinexpression of three xenobiotic efflux pumps [170] Similarlya constitutive androstane receptor is also identified as positiveregulator of p-glycoprotein [206] The p-glycoprotein (p-gp) multidrug resistance protein and the breast cancerresistance protein (BCRP) are members of the ATP bindingcassette transporter family of proteins that is responsiblefor rapid transportation of drug across the cell membranethat regulates both uptake and efflux [215] However over-expression of these transporters particularly p-gp affects thedistribution of drugs in various parts of the body includingthe central nervous system (CNS) It is also responsible forthe development of drug resistance in cancer cells [215]

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

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BioMed Research International

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MEDIATORSINFLAMMATION

of

BioMed Research International 21

However reduced function and expression of gPgPresult in slow clearance of neurotoxic peptides such asamyloid beta peptide from the neuronal cells [215] P-gpis thought to send back circulating toxic compounds frombrain to blood circulation Moreover drugs recognized byefflux transporters including ATP binding cassette trans-porter such as p-glycoprotein (MDR1ABCB1) breast cancerprotein (BCRPABCG2) and multidrug resistant protein-4 (MRP4ABCC4) show low permeability across the brainbarrier resulting in low distribution to the brain [216] Thusbrain to blood efflux transport system also plays an importantrole in the clearance of endogenous neurotropic compoundssuch as prostaglandin and beta amyloid whose reduction isrelated to disorders of the CNS [216] Similarly dolichyl-Pin the brain plays an important role in the depression ofthe P-gp at BBB that results in increased pump functionat the BBB [14] Therefore use of neuroprotective agentthat is brain derived neurotropic factor (BDNF) whichprotects neurons against these effects could be of immensetherapeutic importance [217] Thus development of a drugdelivery system that can cross BBB may have significanttherapeutic advantage [217] However preparation of mag-netically guided nanocarrier may provide viable approachfor targeting BDNF across BBB These could transmigrateacross the BBB However such nanocarriers can be usedas potential therapeutic carriers to treat opiate addictionneurotoxic effects and synaptic degeneration in patients [217]Therefore few drugs which maintain blood to brain influxtransport systems for example an amino acid transporterLat1SLC 7A5 and organic cation transporter show CNSdelivery [216] Thus brain to blood efflux transport systemsalso play an important role in the cerebral clearance ofendogenous neurotoxic compounds such as prostaglandinsand beta amyloid [216]

66 Cholesterol Mediated Cationic Solid Lipid NanoparticlesDelivery System Lipid-based nanoparticle formulations areused as drug carriers [218] for peptides and proteins [219]and for oral administration of drugs [220 221] Lipid-derived nanoparticles are also used for immunostimulatoryRNA adjuvant [222] and transdermal drug delivery [223](Table 3 Figure 5) Similarly cationic lipidDNA lipoplexes[224] PLGA-based nanoparticulate systems [225] light-sensitive lipid-based nanoparticles [226] and multifunc-tional lipid-coated nanoparticle are used for cancer therapy[227] while polylipid nanoparticles [228] and cyclen-basedcationic lipids are used for more efficient gene deliverytowards tumor cells [229] Similarly both functional lipidsand lipoplexes are used for improved nonviral vector genedelivery [230 231] (Figure 5 Table 3)

Similar to lipid nanoparticles mainly cholesterol medi-ated cationic solid nanoparticles (CSLNS) were formulatedwith esterquat (EQ1) and stearylamine which act as positivelycharged external layers on hydrophobic internal cores ofcacao butter Thus an increase in the weight percentage ofcholesterol and EQ1 promote the uptake of SQV-CSLNSby HBMECs and high content of cholesterol MoreoverEQ1 in SQV-CSNLS increased the BBB permeability of

SQV [232] Therefore cholesterol mediated SQV-CSNLScan be more efficacious drug delivery system for braintargeting delivery of antiviral agents [232] Layer-by-layerthin film of reduced graphene oxide and gold nanoparti-cles are used in laser-induced desorptionionization massspectrometry for effective detection and drug delivery [233]Similarly diketopiperazine-based motif is considered as anovel brain shuttle for the delivery of drugs with lim-ited ability to cross the blood brain barrier [225 234]It works as an ideal candidate for the retinoid develop-ment of new therapeutic agents Its derivatives also showremarkable neuroprotective and nootropic activity [234]in experimental animal models [234] Similarly activatedastrocytes protect neurons from toxic substances and can beused for protection of CNS from various chemotherapeuticagentsdrugs Normally these are used for treatment offatal disease [235] In addition there is an urgent need ofnanovehicles for intracellular delivery systems [236] Furtherstem cell therapy combined with technology could becomea promising tool to deliver drugs to brain tumors moreefficiently (Table 3)

67 SiRNA Delivery System Liposomal siRNA nanocarriersare used for cancer therapy [237 238] and to suppress effectsof oncogenes [239] (Table 3) though it is a great challenge touse multifunctional nanoparticles delivering small interfer-ing RNA to overcome drug resistance in cancer cells [240]These liposome-siRNA peptide complexes are prepared byincorporating a small peptide that binds SiRNA and acetyl-choline receptors (AchRs) acting as a molecular messengerfor delivery to neurons and cationic liposomes that protectSiRNA peptide complexes from serum degradation [241]Thus LPSCs (liposome-SiRNA peptide) complexes whichdeliver PrP SiRNA specifically to Ach-R-expressing cells sup-press PrPcopy expression and eliminate PrP siRNA throughoutthe brain [241] LPSc were found to be effective vehicles fordelivery of PrP and other SiRNA specifically to neurons totreat neuropathological diseases [241] Similarly small RNAsof virus and host origins have been found to modulate virushost interactions by RNA interference (RNAi) leading toantiviral immunity or viral pathogenesis [242]These distinctclasses of small RNAs guide specific gene silencing at bothtranscriptional and posttranscriptional levels and serve asspecificity determinants [242] Similarly nucleolin-targetingliposomes guided by aptamer AS1411 are used for the deliveryof siRNA for the treatment of malignant melanomas [243]Anti-VCAM-1 SAINT-O-Somes enable endothelial-specificdelivery of SiRNA and downregulation of inflammatorygenes in activated endothelium in vivo [244] Similarlylipopolyplexes comprising imidazoleimidazolium lipophos-phoramidate histidinylated polyethyleneimine and siRNAare used as efficient formulation for siRNA transfection [245]However for systemic delivery of siRNA and enhanced endo-somallysosomal escape distearoyl phosphoethanolamine-polycarboxybetaine lipids are used [243] Further additionof polypropylene glycol to multiblock copolymer optimizessiRNA delivery [246] However tumor priming enhancessiRNA delivery and transfection in intraperitoneal tumors

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

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[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

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[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Medicinal ChemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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MEDIATORSINFLAMMATION

of

22 BioMed Research International

[247] while O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex is administered by convection-enhanced delivery to rat and porcine brains [248] Moreoverdifferent lipidic systems are used for in vivo siRNA delivery[249]

68 Colloidal Drug Carriers Colloidal drug carriers suchas liposomes and nanoparticles are used to improve thetherapeutic index of both established and new drugs bymod-ifying their distribution applications (Table 3) [250] Theseare proved to be better drug delivery systems [178] becauseindirectly they increase drug efficacy by reducing theirtoxicity [250] Colloidal drug carrier systems such as micel-lar solutions (microemulsions) vesicles and liquid crystaldispersions as well as nanoparticle dispersions consisting ofsmall particles of 10ndash400 nm diameters in size are used tooptimize drug loading and release These show long shelf-life and low toxicity [178] Similarly microemulsions are usedto deliver new classes of active molecules such as peptidesand proteins genes and oligonucleotides The incorporateddrug participates in the microstructure of the system but itsstructure is affected due to molecular interactions especiallyif the drug possesses amphiphilic andor mesogenic prop-erties [178] These systems form spontaneously combiningappropriate amounts of a lipophilic and a hydrophilic ingre-dient as well as a surfactant and a cosurfactant They mayalso offer alternative modes for more conventional drugssuch as highly hydrophobic small molecules The formationof a ME is accompanied by a significant increase in theinterfacial area The required very low interfacial tensioncannot be realized by only one surfactant The additionallyused cosurfactant penetrates the amphiphilic interfacial layerand increases its curvature and fluidity [251 252] Two typesof MEs are differentiated bicontinuous ones and MEs withdroplet like structure The droplet structures are formingdepending on the major compounds water-in-oil (wo) andoil-in-water (ow)MEs having colloidal phases in the range of10ndash100 nm which are colloidal structures such as solubilizedmicellar systems These are also known as swollen micellesIn addition colloidal or particulate carrier systems widelyinteract with cell microenvironment and are widely usedas cargo carriers in vaccine therapies of CNS pathogens(Table 3) More specifically polymeric particulate systemscan be used as effective delivery tool by providing control overspatial and temporal distribution of cargos after systemic orlocalized administration along with enhancing their stabil-ity profile [253] Curcumin-loaded solid lipid nanoparticlescan control drug release and improve bioavailability Theseshowed high drug entrapment efficiency and loading capacity[254] Further there is a need for optimizing different drugdelivery systems for better therapeutic aids to the patients[255]

69 Liposomes Liposomes are widely used as carriers ordelivery vehicles for therapeutic agentsdrugs to send themat specific sites inside human body These are vesicles ofphospholipids that form spontaneously in solutions and arecapable of trapping dissolved particles in solutions As most

of the drugs do not cross the BBB hence for its deliveryliposome technology is proved highly applicable (Figure 6)Further advancements in liposomal drug delivery have pro-duced long circulating and highly stable drug formulationsHowever by making numerous improvements a number ofliposome-based formulations are being made which effec-tively work as drug carriers Liposomes are biodegradableliberating the charged molecules slowly when they degradein the organism Many of them are commercially availableand some are in the developing phase and are undergoingclinical trials These formulations can minimize systemicexposure after transportation of drug and its biodistributionin target organs cells or compartments within the cells withor without expression of target recognition molecules onliposome membranes [245] However to increase the clinicaluse of liposome drug interaction and liposome depositionmechanism lipid-drug association ismore feasible formakingthe drug more accessible in to the brain for various therapiesMoreover liposomal drug delivery methods are widely usedfor brain tumor and antimicrobial therapeuticsThese are alsohighly applicable for gene transfer into cells that could beobtained by appropriate selection of the gene transfer vectorand mode of delivery

Liposomes are lyotropic liquid crystals composed ofrelatively biocompatible and biodegradable materials andconsist of an aqueous core entrapped by one or more bilayersof natural andor synthetic lipids These are composed ofnatural lipids and are biodegradable biologically inert andweakly immunogenic and produce no antigenic or pyrogenicreactions and show limited intrinsic toxicity Liposomesare versatile drug carriers which can be used to controlretention of entrapped drugs in the presence of biologicalfluids (Table 3) These showed controlled vesicle residence inthe systemic circulation in the body and enhanced vesicleuptake by target cells Therefore drugs encapsulated inliposomes are expected to be transported without rapiddegradation and minimum side effects to the recipients Dueto more dispersive property and stability in both acidic andbasic conditions liposomes are considered well-establishedcarriers and have wider applications in biomedicine andfood industry [256] Unfortunately therapeutic efficacy ofliposomes remains limited due to the slow diffusion ofliposomal particles within the tumor and its limited release oruptake of drug in many cases [257] However reformulationof drugs in liposomes will provide an opportunity to enhancethe therapeutic indices of various chemical agents mainlythrough the alteration of biodistribution (Table 3)

Liposomes and polymersomes are generally used ascarriers for encapsulating compounds in particular drugs fordelivery However synthesis of nanoparticles with an empha-sis on the use of self-assembled systems such as micellesmicroemulsions nanoemulsions and liposomes can increasethe drug distribution bioavailability and its targeted action[258] Thus for better chemotherapeutics liposomal drugcarriers are used for controlled release of active drug formu-lations at a predetermined rate However for achieving morestable circulation liposomes are conjugated with carboxyl-terminated CRPPR peptide and nontargeted liposomes toenhance the drug delivery into tumors It shows affinity

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

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[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

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[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

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AddictionJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 23

for the receptor neuropilin-1 (NRP) is and expressed onboth endothelial and cancer cells [257] Similarly carboxyl-terminated RXXR peptide conjugated to liposomes retainslong circulation enhances drug binding and internalizationand finally cut down toxicity [257] However for targeting ofdrugsmany drug carriers like serumproteins immunoglobu-lins synthetic polymers liposomes niosomes microspheres(Figure 6) erythrocytes reverse micelles pharmacosomesand monoclonal antibodies are synthesized and used

However for delivery of anticancer drugs to the targetsite and for more effective treatment specific delivery sys-tems are generated Further anticancer drugs are designedthat work with mild hyperthermia-mediated triggering andtumor-specific delivery Hence thermosensitive liposomes[258] are made by using thermosensitive polymers [259]Further targeted and ultrasound triggered drug deliverysystems are made in which liposomes are comodifiedwith cancer cell-targeting aptamers and thermosensitivepolymers [259] Further to enhance the thermosensitivedrug release elastin-like polypeptide (ELP) is incorporated(thermally responsive phase transition peptide) into thedipalmitoylphosphatidylcholine- (DPPC-) based liposomesurface [260] Additionally cyclic arginine-glycine-asparticacid (cRGD) binds to120572V1205733 integrin which is overexpressed inangiogenic vasculature and tumor cells and was introducedon the liposome Moreover ELP-modified liposomes withthe cRGD targeting moiety were prepared using a lipid filmhydration method and doxorubicin (DOX) was loaded intothe liposome by the ammonium sulfate-gradient methodThe cRGD-targeted and ELP-modified DOX-encapsulatedliposomes (RELs) formed spherical vesicles with a meandiameter of 181 nm The RELs showed 75 and 83 DOXrelease at 42∘C and 45∘C respectively The stability of RELswas maintained up to 12 h without the loss of their ther-mosensitive function for drug release These stable target-specific and thermosensitive liposomes are promisingly usedto enhance therapeutic efficacy (Figure 6) of anticancer drugsand are applied alongwith a relevant external heat-generatingmedical system (Table 3 Figure 4) [260]

Similarly for the treatment of blood malignancies tar-geted particulate drug delivery systems are developed Thesecould employ targeted liposomal formulations for B cellmalignancies [261] For example liposomal encapsulation ofantineoplastic agents such as AD 198 has been made thatis proved to be superior to doxorubicin [261] SimilarlyPEG-coated irinotecan cationic liposomes have shown bettertherapeutic efficacy against breast cancer in animals [262]Furthermore many improved liposomal formulations suchas loaded ethosomes to carry drugs across human skin [263]terbinafine HCL liposomes for cutaneous delivery [264]and curcumin-loaded cationic liposomes are prepared forvarious cancer therapies [265] Similarly novel transferrinembedded fluorescent magneto-liposome nanoformulationswere made which have shown enhanced blood brain barriertransmigration [266] Further liposomes comodified withcholesterol anchored cleavable PEG and octaarginines weremade for targeted drug delivery [267] In addition PEGyla-tion improves the receptor mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexes

[268] Further electrostatically driven complexation of lipo-somes with a star shaped polyelectrolyte was used to havelow toxicity multiliposomal assemblies [269] However toenhance surface functionalization different anchoring lipidswere used via Staudinger ligation [270]

However for effective cancer therapeutics nanoscaledrug delivery systems such as liposomes polymers andother nanoparticles were developed that provide potentialsolutions and are currently in use Moreover all currentliposomal drugs were evolved from a number of drugdesigns and strategies tested in the laboratory for improvedbiodistribution within the body Moreover liposomes afforda unique opportunity to deliver the drugs into cells byfusion or endocytosis mechanism and practically any drugthat can be entrapped into liposomes irrespective of itssolubility However 120572-helical peptides synthesized de novoinduce aggregation of various kinds of cells by focusingon physicochemical properties such as hydrophobicity netcharges and amphipathicity Further liposomal formula-tions having cell-aggregating peptides lead to aggregationof living cells without cytotoxicity [271] Moreover peptidehydrophobicity is the key factor that determines capabilitiesfor cell aggregation while peptide net charges contributeto nonspecific electrostatic interactions with cells Theseamphipathic peptides tend to exhibit cytotoxicity such asantimicrobial activity and hemolysis which are competitivewith cell-aggregation capabilities In addition aggregation ofartificial anionic liposomes appears to be mainly determinedby electrostatic interactions

However drugs with wide variations in lipophilicitiescan be encapsulated in liposomes either in the phospholipidbilayer in the entrapped aqueous core or at the bilayerinterface Because in liposomes water soluble and fat-solublemedications are trapped inside two different layers and oneend remains inside the water while another end or the drugremains trapped inside aggregation of hydrophobic endsHowever in most of the liposomes one end of each moleculeis water soluble while the opposite end is water insoluble[272] But in few cases liposomes are found to attach tocellular membranes and fuse with them and simultaneouslyrelease drugs into the cell [273] Interestingly these areinternalized by phagocytic cells and phospholipid walls areacted upon by lysosomes and the medication is releasedHowever sometimes the large size of the liposomes producesmicroembolisms that gave a false impression of brain uptake[251] Therefore for solving the brain drug delivery problemlipidization of the drug should be made For this purpose awater soluble drug should be converted into a lipid solubledrug by changing the functional groups However to diffusethe restriction imposed by BBB conversion of water solubledrug into lipid soluble prodrug could be a complete solution[274]

Liposomes are better suited for assessing their targetableproperties because of the ease of modifying their surfacewhen compared to other drug carriers such as nanoparticles[206 275] and microemulsions [276 277] (Table 3 Figure 6)However various approaches have been attempted to increasedrug accumulation internalization and therapeutic efficacy[257] Therefore various biodegradable materials are used to

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

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MEDIATORSINFLAMMATION

of

24 BioMed Research International

form liposomes for different purposes A palmitic cationicliposomal in situ gel protects from external compounds andkeeps the drug intact in its natural form [278] Similarlypolyglycerol coating to plasmid DNA lipplex is used for theevasion of the accelerated blood clearance phenomenon innucleic acid delivery [279] Further to achieve targetablecarrier properties various noncovalent associations of cell-specific antibodieswith liposomes are beingmade [280] Sim-ilar covalent attachment of poly- and monoclonal antibodiesto the liposomes [281 282] and coating of liposomeswith heataggregated immunoglobulins M (IgM) are also done [283]Similarly natural [284] and synthetic [285] glycolipid [286287] glycoprotein bearing liposomes [288] and transferrincoated paclitaxel loaded [289] lysozyme liposomes [281]and neuroipilin-1-targeted liposomes were made to enhancedelivery and bioefficacy of drugs [257] More specificallycompounds entrapped into the liposomes are protected fromthe action of external media particularly enzymes [290] andinhibitors [291] However RGD-lipid conjugate-modifiedliposomes [292] are used for enhancing siRNA delivery inhuman retinal pigment epithelial cells [293] (Table 3)

However liposomal nanoparticles are proved to be mul-tifunctional tools [258] to carry various drugs for can-cer therapy These liposomal siRNA nanocarriers are alsoused in tumor therapy [239 246] while enhanced endo-somallysosomal escape by diesteryl phosphoethanolamine-polycarboxybetaine lipid is used for systemic delivery ofsiRNA [294] Similarly cationic liposome mediated deliveryof FUS1 and hil12 is used to treat human lung cancer Theseare also used as transfecting agents of DNA in gene therapy[290] Moreover endothelial targeting of liposomes encap-sulating SODcatalase EUK-134 alleviates acute pulmonaryinflammation [295] However to optimize the applicationpolymeric core-shell [296] amphiphilic block copolymer[273] molecular imprinted polymers are used for preparingadvanced drug delivery devices [297] Similarly supramolec-ular drug delivery systems are used formembrane permeabil-ity with bacterial porins [298] and bioadhesive microspheresare used for controlled drug delivery system [299] Moreoverall existing liposomal delivery systems are experimentallyconfirmed which can transfer sizable amount of drug Thiswill optimize drug action and target specificity in diseasedtissues in particular region of brain Moreover efforts havebeen made to increase the specificity of carriers to carrydrugs to the target organs mainly to cells or within variouscellular compartments However lipidization of the drugfunctions is considered as a noninvasive approach to solvingthe toxicity related brain drug delivery problem Howeverto optimize the drug action water soluble drug compoundcould be made lipid soluble by making slight change in itsfunctional groups This could uplift transport restriction byconversion of water soluble drug into lipid soluble prodrug[300] However polysorbate 80 a detergent is used to disruptthe BBB which also act as a drug stabilizing agent andattributes detergent effects to nanoparticles that assist indrug delivery (Figure 4) But a large size of the liposomesproducesmicroembolisms and obstructs the drug uptake andgives a false impression [251] Further modular organizationof immunoliposome technology enables a combinatorial

approach in which a repertoire of monoclonal antibody seg-ments can be used in conjunction with a series of liposomaldrugs to yield a new generation ofmolecularly targeted agents(Table 3) [301]

610 Micelles Micelle is an aggregate of surfactant moleculesdispersed in a liquid colloid A typical micelle in aqueoussolution forms an aggregate with the hydrophilic ldquoheadrdquoregions in contact with surrounding solvent sequesteringthe hydrophobic single-tail regions in the micelle centreThis phase is created by the packing behavior of single-tailed lipids in a bilayer It is formed by filling in volumeof the interior of a bilayer and area per head group forcedon the molecule by the hydration of the lipid head groupMicelles are formed if one of the two fatty acyl chains isremoved from the phosphoglycerides by hydrolysis forminga lysophospholipids It forms a normal-phase micelle or oil-in-water micelle (Figures 4 and 6) Micelles are rarely formedfrom natural phosphoglycerides whose fatty acid side chainsare too bulky to fit into the interior of a micelle Normallyin aqueous solutions common detergents and soaps formmicelles that behave as tiny ball bearings thus giving soapsolutions thin slipper fed and lubricating prospective Natu-rally biomembrane contains cholesterol glycolipids and pro-teins but these possess hydrophobic core that separates twoaqueous solutions and acts as a permeability barrier Morespecifically in phospholipids and sphingolipids and hydro-carbons tails of fatty acids side chains are hydrophobic whileheads are strongly hydrophilic Moreover phospholipids areamphipathic in nature are quite interactive and form a sealedcompound surrounding an internal aqueous space Hence asuspension of phospholipids upon its mechanical dispersionin aqueous solution aggregate to form spherical micellesliposomes and phospholipid bilayerThephospholipid bilayeris the basic structural unit of nearly all biological membranes(Figure 6)

Contrary to this inverse micelles have the head groups atthe centre with the tails extending out and forming water-in-oil micelle Micelles are approximately spherical in shape butits other shapes such as ellipsoids cylinders and bilayers arealso possible Both shape and size of a micelle are a functionof the molecular geometry of its surfactant molecules andsolution conditions such as surfactant concentration tem-perature pH and ionic strength However micelle chemicalcomposition total molecular weight and block length ratioscan be easily changed which allows control of the size andmorphology of the micelles Further functionalization ofblock copolymers with cross-linkable groups can increasethe stability of the corresponding micelles and improve theirtemporal control [302 303] However micelles formed byself-assembly of amphiphilic block copolymers (5ndash50 nm)in aqueous solutions have wider drug delivery applications[290] These micellar structures physically entrapped thedrug and transported it to the target area and releasedrequired concentrations It exceeds due to intrinsic watersolubility Further the hydrophilic blocks form hydrogenbonds with the aqueous surroundings and form a tight shellaround the micellar core As a result the contents of the

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

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AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 25

hydrophobic core are effectively protected against hydrolysisand enzymatic degradation [302]

Polymeric micelles are new drug carrier systems whichare used for drug targeting of anticancer drugs to solidtumors It is a macromolecular assembly composed of aninner core and an outer shell and most typically is formedfrom block copolymer that is suitable for encapsulation ofpoor water soluble hydrophobic anticancer drugs Polymericmicelles are of nanorange in size and show stability andlongevity in vivo that is why these areused for targeted deliv-ery at the tumor sites by passive mechanism where they showenhanced permeability and retention effect Other character-istics of polymeric micelles such as separated functionality atthe outer shell are useful for targeting the anticancer drug totumor by active mechanisms [303] Polymeric micelles areconsiderably more stable than surfactant micelles and cansolubilize substantial amounts of hydrophobic compounds intheir inner core Polymeric micelles also enhance pharma-cological activity of drugs [304] and show potential med-ical applications especially in cancer chemotherapy [305](Figure 6 Table 3) Due to their hydrophilic shell and smallsize polymeric micelles accumulate in tumoral tissues andpersist for longer duration [301 306] Polymeric micellescan be conjugated with many ligands such as antibodiesfragments epidermal growth factors 120572

2-glycoprotein trans-

ferrin and folate to target micelles to cancer cells Howeverpolymeric micelle could deliver drugs by both passive andactive mechanisms [303 304] These successfully obstructtumor angiogenesis and find potential targets of anticancerdrugs [303]

7 Cellular Mechanisms for Drug Targeting

BBB restrict entry of most of the biomolecules mainly pro-teins peptides carbohydrates and vaccines Hence deliveryof therapeutic peptides and proteins to the central nervoussystem is the biggest challenge for development of moreeffective neuropharmaceuticals [307] BBB is impermeableto most molecules and most of the proteins found inthe plasma are not able to cross the blood brain barrierbecause of their size and hydrophilicity But few peptidehormones which regulate body metabolism and normalfunctions of catabolites as both insulin and transferrinconcentration varies in plasma and uptake of these peptidesin the brain is greater than expected based on their size andlipid solubility These are carried to the brain by specifictransport processes mainly membrane bound efflux pumpsand channels The major transport mechanism which carriesproteins and hormones is receptor mediated transcytosisHowever therapeutic agents may reach to the target sitesat intracellular locations The brain capillary endothelialcell is highly enriched in receptors for these proteins andfollowing binding of protein to the receptor a portion ofthe membrane containing the protein-receptor complex isendocytosed into the endothelial cell to form a vesicleAlthough the subsequent route of passage of the proteinthrough the endothelial cell is not known eventual releaseof intact protein on the other side of the endothelial cell

is highly useful because blood brain barrier is impermeableto these molecules [307] During delivery process a portionof compound was lost due to ineffective partitioning acrossthe membrane Hence partitioning across the membrane iswidely concerned with polarity lipophilicity of moleculesthat attributes easy passage across the membrane Howeveramphiphilic derivatives of a peptide are easily delivered intothe brain These are designed to self-assemble into nanofibrewhich in the active peptide epitope is tightly wrapped aroundthe nanofibre core [307] Recently several neuroprotectiveproteins andpeptides of potential therapeutic value have beendesigned that showed effective and safe transcapillary move-ment into the brainTherefore most promising drug deliverythrough brain capillaries is only possible by augmentation ofpinocytotic vesicles because it is a fully noninvasive methodThis is a cellular mechanism which assist in delivery of largemolecules of neurotherapeutic potential by conjugating themwith peptidomimetic ligands Later on these molecules bindto selected peptide receptors which internalize and transportit in small vesicles across the cytoplasmic brain capillarybarrier These conjugates are found functionally active andeffective in animal models of neurological disease Similarlyneurotrophin a brain derived neurotrophin a brain-derivedneurotrophic factor easily passes through BBB and hasgreat therapeutic value Interestingly short peptides withhydrophilic nature have shown favorable safety profiles inbrain and found neuroprotective after come across the BBBHowever exogenous recombinant human erythropoietin wasproved to be beneficial in treating global and focal cerebralischemia and reducing nervous system inflammation inexperimental animals Moreover other than neuroprotectivecompounds monoclonal antibodies are also used to passthrough BBB by receptor mediated endocytosis mechanismSimilarly metallothionins a superfamily of highly conservedlow molecular weight polypeptides play a significant role inthe regulation of concentration of essential metals which arealso internalized by receptormediated endocytosis Howevervariable efficiencies of endocytosis mechanisms such asintracellular trafficking and release of therapeutic agents into the cytoplasm are important aspects in drug deliveryand therapeutic potency There are many possibilities afterdiffusion and translocation of the therapeutic agents Theseremain susceptible targets of certain catalytic enzymes orphysically partition into the nucleus or in any other sub-organelles that may also alter its actual activity Furtherexcess delivery of therapeutic agentsmay create a competitiveproblem to some other biomolecules that may hinder normalfunctions of cells cellular organelles enzymes and signalingmolecules In addition metabolic wastes may also over bur-den the cell cytoplasm that inhibits so many normal cellularfunctions and give rise to drug induced adverse effectsHowever use of nanoparticles may solve this problem dueto controlled release of drugs in required quantity These caneasily cut down concentration of metabolic waste materialsby masking the therapeutic agents from its biological envi-ronment Nanoparticles allow controlled (sustained) drugrelease from the matrix determine required bioavailabilityand show reduction of the dosing frequencyThese are provedto be most successful drug carriers due to their high stability

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

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[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

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convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

26 BioMed Research International

high carrier capacity and feasibility of incorporation of bothhydrophilic and hydrophobic substances into brain or insidecells These also show feasibility to deliver drugs by followingvariable routes of administration including oral applicationand inhalation

Normally twomechanisms are employed to ascertain theinternalization of biomolecules mainly liquids are pouredin by pinocytosis and solids by phagocytosis Howeverthere is carrier mediated delivery of drugs by nanoparti-cles and these are ingested by cells from the medium orfrom any microenvironment surrounding the cell Howevernanoparticles are pouring in by receptor mediated endo-cytosis that could operate by membrane manipulation toenvelope and allow materials to absorb inside Thereforeit is clearer that nanoparticles get inside the cells by threedifferent mechanisms that is phagocytosis pinocytosis andreceptor mediated endocytosis Furthermore phagocytosisis associated with few cell types such as macrophagesneutrophils and dendritic cells which can absorb materialsof micrometer in size that is 10120583m in diameter Similarlypinocytosis is a universal mechanism which occurs in allcell types and it delivers different types of liquids having asubmicron size and substances in solution inside the cellMore specifically larger sized nanoparticles are taken up bythe cell by phagocytosis while smaller ones are absorbed bypinocytosis and most of them are ingested by all cell typesTherefore both types of nanoparticles have important butseparate advantages Furthermore there is another mecha-nism which is known as absorptive-mediated transcytosisthat is especially used to traverse polycationic proteins andlectins This is a nonspecific process in which proteins areadsorbed on the endothelial cell membrane based on chargeor affinity for sugar moieties of membrane glycoproteinsIts subsequent transcytotic events are probably similar toreceptor mediated transcytosis However overall capacity ofabsorptive-mediated transcytosis is far greater than that ofthe receptor mediated endocytosis because the number ofreceptors present in the membrane does not limit it Thuscationization may provide a mechanism for enhancing brainuptake of almost any protein

8 Conclusion

Because of limits imposed by structural barrier (BBB) thedelivery of therapeutic drugs to brain remains a challengingtask to treat patients suffering from tumors virus generatedneuronal infections and neurodegenerative diseases How-ever for proper medication of patients several approacheshave been developed and used for direct and indirect deliveryof drugs to the brain But sometimes direct injectionsor convection-enhanced delivery of drug or cerebrospinalfluid or intranasal delivery creates problems to the patientor remains unsuccessful These approaches are proved tobe very much unsafe highly invasive and short lastingTherefore targeted molecular based therapies are developedfor treatment of brain tumors that could deliver the antitumordrugs to the target sites and stop aberrant signaling pathwaysin the brain Further vascular route should be improved

to make it more promising for drug delivery to the brainbecause it allows a widespread diffusion of the infuseddrug throughout brain and covers a large surface areaHence drugs that could find their way through nonbarrierregions will be preferred to lower down the risk of neuronalinjuries nondelivery and therapeutic failures Hence thereis a need to generate new nanosized carrier vehicles thatcould easily pass through systemic microvascular beds foundin blood capillaries and endothelial cells for safe delivery ofpharmaceuticals Therefore natural formulations should bedeveloped that could passively pass through discontinuoustight junctions or with the help of plasmalemmal vesiclesand windows occurring in endothelial cells Therefore novelstrategies that could overcome the intrinsic limitations of theBBB are highly desirable

Further to lower down the risk of nanoparticle generatedcytotoxicity and invasiveness biodegradable biomaterialsshould be used to minimize toxic effects in the brain Bioma-terials used formaking nanoparticle should be biocompatibleand must have very short half-life Therefore biodegradablepolymers like polylactic acid polycaprolactone poly(lactic-co-glycolic acid) the poly(fumaric-co-sebacic) anhydridechitosan andmodified chitosan as well as solid lipids shouldbe used to prepare nanoparticles Further to reduce thedrug toxicity and to minimize its adverse effects simplerdrug conjugates like doxorubicin can be attached Moreoveractive drug molecules can be coupled to a desired protein orpeptide that increases its circulating life solubility stabilityand antigenicity Further various nanoprodrugs should beprepared by using spontaneous nonemulsifiable biodegrad-able antioxidants and vitamins to enhance therapeutic effi-cacy of drugs in the oxidative tumor microenvironment[308] Moreover modification of nanoparticle surface withcovalently attached targeting ligands or by coating withcertain surfactants is essential for receptor mediated uptakeor adsorption of specific plasma proteins after injection inhuman A proper avidity is also required for nanoparticles toreach the brain parenchyma and it should be consistent withtranscytosing antibodies that bind to TfR [309] It can be usedfor delivery of a great variety of drugs including anticanceranalgesics cardiovascular protease inhibitors and severalmacromolecules into the brain after intravenous injectionin animals In addition chimeric peptides lipids and beta-cyclodextrin carriers can be used as colloidal drug carriers[169] Further for systemic administration transferrin (Tf)bound gold nanoparticles are proved highly useful for trans-port of therapeutic agents into the brainTherefore advanceddrug delivery systems are to be developed for transport ofpotential biopharmaceuticals to treat CNS related disorderspathogenesis and neoplasticity More specifically among allexisting drug delivery methods nanotechnology holds greatpromise for a noninvasive therapy of brain tumors and otherCNS diseases

Moreover noninvasive methods like contrast enhancedmicrobubble ultrasound should be preferred for drug deliv-ery because generation of microbubbles leads to drugperfusion enhancement in nervous tissue It also directlyincreases amount of drug delivered into the brain Furtherreceptor mediated delivery systems are used for delivery of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

[1] M Kinoshita ldquoTargeted drug delivery to the brain usingfocused ultrasoundrdquo Topics inMagnetic Resonance Imaging vol17 no 3 pp 209ndash215 2006

[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

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[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

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[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

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30 BioMed Research International

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[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

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[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

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[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

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[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 27

proteinspeptidal drugs However methods such as recep-tor mediated endocytosis loaded microbubble enhancedfocused ultrasound and cholesterol mediated cationic andsolid lipid nanoparticles delivery system SiRNA delivery sys-tem colloidal drug carriers liposomes and micelles shouldbe reinvestigated for their further advancements to enhancethe targeted drug delivery of therapeutic agents Furthersafer and noninvasive methods such as micelles formedfrom natural phosphoglycerides are used to deliver the drugSimilarly various types of liposomes such as PEGylatedliposomes niosomes and aquasomes are specially used forpeptidal drug delivery Further combination therapies areto be developed for tumor ablation [144] and inhibitionof cancer associated mutations by peptide masking [310]Further intracarotid infusion of bradykinin (BK) nitricoxide (NO) donors or agonists of soluble guanylate cyclase(sGC) and calcium-dependent potassium K(Ca+) channelsenhance drug delivery into the brain These were found to bemore effective and safer to treat tumor patients [21] Furtherfor targeted drug delivery a series of amino acids dipeptidediester prodrugs of NO donating oleonotic disruptive are tobe designedThese should be practiced to find an appropriatesolution ofCNS related pathogenicity andneurodegeneratingdiseases Similarly new hydrogels should be prepared fortransdermal delivery of drugs to treat skin and dermalcancers [311] Furthermore fine nanocarriersvehicles such asmembrane transporters and ABC cassettes molecular drugtransporters or delivery vehicles are to be developed Inaddition natural transporters are favored to support transportof drugs nourishments to maintain vital brain functions Inaddition role of various drug transporters and permeablitiz-ers must be reinvestigated

Therefore for active distribution of drug its carrier load-ing targeting and transport foolproof drug delivery systemsare to be developed In addition its interactions with biolog-ical barriers should be properly investigated in experimentalanimals as well as in in vitro systems Moreover advancedmethods are to be developed for easy delivery of healerspeptides proteins growth factors vaccines and antibodiesfor treatment of CNS diseases and disorders Further thereseems to be an instant need of new smaller pharmaceuticalshaving target specific designs Hence a long term planningis required for stepwise upgradation of pharmaceuticalsand to have design of highly absorbable drugs Furthertechnologically upgraded simpler drug delivery systems areto be developed for making much faster strategic defenseagainst different types of tumors cancers disorders and viraldiseases It may not only help to deliver the pharmaceuticalsbut also to assist in finding new signaling pathways thatmay help in diagnosis assimilation of drugs and its activefunctions in infectious tissues Hence new absorbable drugdesigns having nanoscale particle size and showing hightarget specificity and transcellular signaling should developThese new drug candidates must be pretested in vitro systemsto find appropriateness of drug action and to authenticatethe behavior of biopharmaceuticals Therefore to fulfill drugdelivery tasks a better understanding is required amongclinicians and immunologists for starting new researchinitiatives to make landmark innovations in the field of

pharmacology molecular biology and clinical therapeuticsof CNS related diseases Hence strong recommendationsare being made to upgrade pharmaceutical technologies bymaking collaborative research efforts to developexplore newinnovative methods for safer drug delivery It is only possibleby making advances in nanobiotechnology and biomaterialsciences to extend the therapeutic use of pharmaceuticalsto cure neurological diseases and CNS impairments Fur-ther biomedical researchers should increase the spectrumof pharmaceuticals by carrying them to targeted locationsby improving the endothelial transport methods There isan essential need of new more innovative noninvasive andnontoxic delivery methods to find quick and easy solution ofneurodegenerative and neuropathological diseases of CNS

Abbreviations

BBB Blood brain barrierCNS Central nervous systemBK BradykininNO Nitric oxidesGC Soluble guanylate cyclaseABC cassettes ATP binding cassettescRGD Cyclic arginine-glycine-aspartic acidDPPC DipalmitoylphosphatidylcholineELP Elastin-like polypeptideNRP Receptor neuropilin-1BDNF Brain derived neurotropic factorp-gp p-GlycoproteinLDL Low-density lipoproteinMRI Enhance magnetic resonance imagingNPs NanoparticlesHAD HIV-1 associated dementiaNACA N acetylcysteine amidePKC Protein kinaseAD Alzheimerrsquos diseaseHIR Human insulin receptorMAb Monoclonal antibodyPEDF Pigment epithelium-derived factorGDEPT Gene-directed enzyme prodrug therapyADEPT Antibody-directed enzyme prodrug

therapy

Conflict of Interests

The author has no conflict of interests The author alone isresponsible for the content and writing of the paper

References

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[2] A R Jones and E V Shusta ldquoBlood-brain barrier transport oftherapeutics via receptor-mediationrdquo Pharmaceutical Researchvol 24 no 9 pp 1759ndash1771 2007

[3] S Senel M Kremer K Nagy and C Squier ldquoDelivery of bio-active peptides and proteins across oral (Buccal) mucosardquo

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

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[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

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[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

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[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

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[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

28 BioMed Research International

Current Pharmaceutical Biotechnology vol 2 no 2 pp 175ndash1862001

[4] A G de Boer I C J van der Sandt and P J Gaillard ldquoThe roleof drug transporters at the blood-brain barrierrdquo Annual Reviewof Pharmacology and Toxicology vol 43 pp 629ndash656 2003

[5] M P Schaddelee H L Voorwinden D Groenendaal etal ldquoBlood-brain barrier transport of synthetic adenosine A1receptor agonists in vitro structure transport relationshipsrdquoEuropean Journal of Pharmaceutical Sciences vol 20 no 3 pp347ndash356 2003

[6] K M Huttunen and J Rautio ldquoProdrugsmdashan efficient wayto breach delivery and targeting barriersrdquo Current Topics inMedicinal Chemistry vol 11 no 18 pp 2265ndash2287 2011

[7] A Seelig R Gottschlich and R M Devant ldquoA method todetermine the ability of drugs to diffuse through the blood-brain barrierrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 91 no 1 pp 68ndash72 1994

[8] M Dadparvar S Wagner S Wien et al ldquoHI 6 human serumalbumin nanoparticlesmdashdevelopment and transport over an invitroblood-brain barriermodelrdquoToxicology Letters vol 206 no1 pp 60ndash66 2011

[9] I Tamai and A Tsuji ldquoDrug delivery through the blood-brainbarrierrdquoAdvanced Drug Delivery Reviews vol 19 no 3 pp 401ndash424 1996

[10] M A Bellavance M Blanchette and D Fortin ldquoRecent advan-ces in blood-brain barrier disruption as a CNS delivery strat-egyrdquo The AAPS Journal vol 10 no 1 pp 166ndash177 2008

[11] O Kuittinen T Siniluoto M Isokangas et al ldquoChemotherapyin conjunction with blood brain barrier disruption in the treat-ment of primary central nervous system lymphomardquoDuodecimvol 129 no 15 pp 1563ndash1570 2013

[12] KK Jain ldquoNanobiotechnology-based strategies for crossing theblood-brain barrierrdquo Nanomedicine vol 7 no 8 pp 1225ndash12332012

[13] P J Gaillard ldquoCrossing barriers from blood-to-brain and aca-demia-to-industryrdquo Therapeutic Delivery vol 1 no 4 pp 495ndash500 2010

[14] J Bian-Sheng J Cen L Liu and L He ldquoIn vitro and in vivostudy of dodichyl phosphate on the efflux of P-glycoprotein atthe blood brain barrierrdquo International Journal of DevelopmentalNeuroscience vol 31 no 8 pp 828ndash835 2013

[15] D Secko ldquoBreaking down the bloodndashbrain barrierrdquo CanadianMedical Association Journal vol 174 no 4 pp 448ndash448 2006

[16] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we knowrdquo Advances in DrugDelivery Reviews vol 71 pp 2ndash14 2013

[17] Q Weng B Wang X Wang et al ldquoHighly water-solubleporous and biocompatible boron nitrides for anticancer drugdeliveryrdquo ACS Nano 2014

[18] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 1 no 116 pp 17ndash25 2014

[19] J Naskar S Roy A Joardar S Das and A Banerjee ldquoSelf-assembling dipeptide-based nontoxic vesicles as carriers fordrugs and other biologically important moleculesrdquoOrganic andBiomolecular Chemistry vol 9 no 19 pp 6610ndash6615 2011

[20] N S Ningaraj M Rao and K L Black ldquoCalcium-dependentpotassium channels as a target protein for modulation of theblood-brain tumor barrierrdquoDrug News and Perspectives vol 16no 5 pp 291ndash298 2003

[21] N S Ningaraj M Rao K Hashizume K Asotra and K LBlack ldquoRegulation of blood-brain tumor barrier permeabilityby calcium-activated potassium channelsrdquo Journal of Pharma-cology and Experimental Therapeutics vol 301 no 3 pp 838ndash851 2002

[22] N S Ningaraj M K Rao and K L Black ldquoAdenosine51015840-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumormodelrdquo Cancer Research vol 63 no 24 pp 8899ndash8911 2003

[23] J Rautio and P J Chikhale ldquoDrug delivery systems for braintumor therapyrdquo Current Pharmaceutical Design vol 10 no 12pp 1341ndash1353 2004

[24] A B Etame R J Diaz C A Smith T G Mainprize KHynynen and J T Rutka ldquoFocused ultrasound disruption ofthe blood-brain barrier a new frontier for therapeutic deliveryin molecular neurooncologyrdquo Neurosurgical Focus vol 32 no1 p E3 2012

[25] H Liu H Yang M Hua and K Wei ldquoEnhanced therapeuticagent delivery throughmagnetic resonance imaging-monitoredfocused ultrasound blood-brain barrier disruption for braintumor treatment an overview of the current preclinical statusrdquoNeurosurgical focus vol 32 no 1 article E4 2012

[26] J Blakeley ldquoDrug delivery to brain tumorsrdquo Current Neurologyand Neuroscience Reports vol 8 no 3 pp 235ndash241 2008

[27] K L Black and N S Ningaraj ldquoModulation of brain tumorcapillaries for enhanced drug delivery selectively to braintumorrdquo Cancer Control vol 11 no 3 pp 165ndash173 2004

[28] R D Fross P C Warnke and D R Groothuis ldquoBlood flowand blood-to-tissue transport in 9L gliosarcomas the role of thebrain tumormodel in drug delivery researchrdquo Journal of Neuro-Oncology vol 11 no 3 pp 185ndash197 1991

[29] A Weyerbrock S Walbridge J E Saavedra L K Keefer andE H Oldfield ldquoDifferential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebralC6 gliomasrdquo Neuro-Oncology vol 13 no 2 pp 203ndash211 2011

[30] A Weyerbrock S Walbridge R M Pluta J E Saavedra LK Keefer and E H Oldfield ldquoSelective opening of the blood-tumor barrier by a nitric oxide donor and long-term survival inrats with C6 gliomasrdquo Journal of Neurosurgery vol 99 no 4 pp728ndash737 2003

[31] M M Yallapu S F Othman E T Curtis B K Gupta M Jaggiand S C Chauhan ldquoMulti-functional magnetic nanoparticlesfor magnetic resonance imaging and cancer therapyrdquo Biomate-rials vol 32 no 7 pp 1890ndash1905 2011

[32] B THunter ldquoBreaching the brainrsquos security systemrdquoConsumersrsquoResearch Magazine vol 84 no 2 p 21 2001

[33] P Hsieh C Hung and J Fang ldquoCurrent prodrug design fordrug discoveryrdquo Current Pharmaceutical Design vol 15 no 19pp 2236ndash2250 2009

[34] J Rautio H Kumpulainen T Heimbach et al ldquoProdrugsdesign and clinical applicationsrdquo Nature Reviews Drug Discov-ery vol 7 no 3 pp 255ndash270 2008

[35] J B Zawilska J Wojcieszak and A B Olejniczak ldquoProdrugs achallenge for the drug developmentrdquo Pharmacological Reportsvol 65 no 1 pp 1ndash14 2013

[36] J Rautio K Laine M Gynther and J Savolainen ldquoProdrugapproaches for CNS deliveryrdquo AAPS Journal vol 10 no 1 pp92ndash102 2008

[37] L Hu ldquoProdrugs effective solutions for solubility permeabilityand targeting challengesrdquo IDrugs vol 7 no 8 pp 736ndash7422004

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 29

[38] J Brask F Albericio and K J Jensen ldquoFmoc solid-phase syn-thesis of peptide thioesters by masking as trithioortho estersrdquoOrganic Letters vol 5 no 16 pp 2951ndash2953 2003

[39] A Novak B Binnington B Ngan K Chadwick N Fleshnerand C A Lingwood ldquoCholesterol masks membrane glycosph-ingolipid tumor-associated antigens to reduce their immunode-tection in human cancer biopsiesrdquo Glycobiology vol 23 no 11pp 1230ndash1239 2013

[40] M S Parker R Sah and S L Parker ldquoSurface masking shapesthe traffic of the neuropeptide y Y2 receptorrdquo Peptides vol 37no 1 pp 40ndash48 2012

[41] W M Pardridge D Wu and T Sakane ldquoCombined use ofcarboxyl-directed protein pegylation and vector-mediatedblood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenousadministrationrdquo Pharmaceutical Research vol 15 no 4 pp576ndash582 1998

[42] W M Pardridge ldquoBlood-brain barrier carrier-mediated trans-port and brain metabolism of amino acidsrdquo NeurochemicalResearch vol 23 no 5 pp 635ndash644 1998

[43] W M Pardridge ldquoCNS drug design based on principles ofblood-brain barrier transportrdquo Journal of Neurochemistry vol70 no 5 pp 1781ndash1792 1998

[44] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of Laryngology and Otology vol 72no 5 pp 377ndash384 1958

[45] J Ali M Ali S Baboota J K Sahni C Ramassamy and L DBhavna ldquoPotential of nanoparticulate drug delivery systems byintranasal administrationrdquo Current Pharmaceutical Design vol16 no 14 pp 1644ndash1653 2010

[46] H R Costantino L Illum G Brandt P H Johnson and SC Quay ldquoIntranasal delivery physicochemical and therapeuticaspectsrdquo International Journal of Pharmaceutics vol 337 no 1-2pp 1ndash24 2007

[47] A J Landau R T Eberhardt and W H Frishman ldquoIntranasaldelivery of cardiovascular agents sn innovative approach tocardiovascular pharmacotherapyrdquo American Heart Journal vol127 no 6 pp 1594ndash1599 1994

[48] R T Jackson J Tigges and W Arnold ldquoSubarachnoid spaceof the CNS nasal mucosa and lymphatic systemrdquo Archives ofOtolaryngology vol 105 no 4 pp 180ndash184 1979

[49] L Illum ldquoIs nose-to-brain transport of drugs in man a realityrdquoJournal of Pharmacy and Pharmacology vol 56 no 1 pp 3ndash172004

[50] T Yamada ldquoThe potential of the nasal mucosa route for emer-gency drug administration via a high-pressure needleless injec-tion systemrdquo Anesthesia Progress vol 51 no 2 pp 56ndash61 2004

[51] G RathnamNNarayanan andR Ilavarasan ldquoCarbopol-basedgels for nasal delivery of progesteronerdquo AAPS PharmSciTechvol 9 no 4 pp 1078ndash1082 2008

[52] W Ying G Wei D Wang et al ldquoIntranasal administrationwith NAD+ profoundly decreases brain injury in a rat modelof transient focal ischemiardquo Frontiers in Bioscience vol 12 no7 pp 2728ndash2734 2007

[53] G Wei D Wang H Lu et al ldquoIntranasal administration of aPARG inhibitor profoundly decreases ischemic brain injuryrdquoFrontiers in Bioscience vol 12 no 13 pp 4986ndash4996 2007

[54] T K Vyas A Shahiwala S Marathe and A Misra ldquoIntranasaldrug delivery for brain targetingrdquo Current Drug Delivery vol 2no 2 pp 165ndash175 2005

[55] J C G Garcia-Rodriguez and I Sosa-Teste ldquoThe nasal routeas a potential pathway for delivery of erythropoietin in thetreatment of acute ischemic stroke in humansrdquo TheScientific-WorldJournal vol 9 pp 970ndash981 2009

[56] B E Bleske E W Warren T L Rice M J Shea G Amidonand P Knight ldquoComparison of intravenous and intranasaladministration of epinephrine during CPR in a canine modelrdquoAnnals of EmergencyMedicine vol 21 no 9 pp 1125ndash1130 1992

[57] W Chieny K S E Su and S F Chang Nasal SystemicDrug Delivery Drugs and the Pharmaceutical Sciences MarcelDekker New York NY USA 1989

[58] B M Paterson P Roselt D Denoyer et al ldquoPET imaging oftumours with a 64Cu labeled macrobicyclic cage amine ligandtethered to Tyr3-octreotaterdquo Dalton Transactions vol 43 no 3pp 1386ndash1396 2013

[59] E M Cornford and M E Cornford ldquoNew systems for deliveryof drugs to the brain in neurological diseaserdquo Lancet Neurologyvol 1 no 5 pp 306ndash315 2002

[60] B Jodeiry M Heidarzadeh S Sahmani-Asl et al ldquoStudy ofintraventricular hemorrhage in VLBW neonates admitted inAl-Zahra Hospital Tabriz Iran Nigerrdquo Nigerian Journal ofMedicine vol 21 no 1 pp 92ndash97 2012

[61] R J Boado Y Zhang Y Wang and W M Pardridge ldquoGDNFfusion protein for targeted-drug delivery across the humanblood-brain barrierrdquo Biotechnology and Bioengineering vol 100no 2 pp 387ndash396 2008

[62] J M Zhang XM Zhao S JWang et al ldquoEvaluation of 99mTc-peptide-ZHER2342 Affibody molecule for in vivo molecularimagingrdquo The British Journal of Radiology vol 87 no 1033Article ID 20130484 2014

[63] X Cui D Cao Z Wang and A Zheng ldquoPharmacodynamicsand toxicity of vasoactive intestinal peptide for intranasaladministrationrdquo Pharmazie vol 68 no 1 pp 69ndash74 2013

[64] F Derakhshan and C Toth ldquoInsulin and the brainrdquo CurrentDiabetes Reviews vol 9 no 2 pp 102ndash116 2013

[65] M Grapp A Wrede M Schweizer et al ldquoChoroid plexustranscytosis and exosome shuttling deliver folate into brainparenchymardquoNature Communications vol 4 article 3123 2013

[66] C Kadoch J Li V S Wong et al ldquoComplement activationand intraventricular rituximab distribution in recurrentcentralnervous system lymphomardquo Clinical Cancer Research vol 20no 4 pp 1029ndash1041 2014

[67] A Zechariah A ElAli T R Doeppner et al ldquoVascular endo-thelial growth factor promotes pericyte coverage of brain cap-illaries improves cerebral blood flow during subsequent focalcerebral ischemia and preserves the metabolic penumbrardquoStroke vol 44 no 6 pp 1690ndash1697 2013

[68] M S Byerly R D Swanson N N Semsarzadeh et al ldquoIden-tification of hypothalamic neuron-derived neurotrophic factoras a novel factor modulating appetiterdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 304 no 12 pp R1085ndashR1095 2013

[69] P Fitchev C Chung B A Plunkett C B Brendler and S ECrawford ldquoPedf amp stem cells niche vs nurturerdquo Current DrugDelivery In press

[70] K Ng V HMabasa I Chow andM H H Ensom ldquoSystematicreview of efficacy pharmacokinetics and administration ofintraventricular vancomycin in adultsrdquo Neurocritical Care vol20 no 1 pp 158ndash171 2014

[71] M L Brady R Raghavan A Alexander K Kubota K Sil-lay and M E Emborg ldquoPathways of infusate loss during

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

30 BioMed Research International

convection-enhanced delivery into the putamen nucleusrdquoStereotactic and Functional Neurosurgery vol 91 no 2 pp 69ndash78 2013

[72] K Nishina H Mizusawa and T Yokota ldquoShort interferingRNA and the central nervous system development of nonviraldelivery systemsrdquo Expert Opinion on Drug Delivery vol 10 no3 pp 289ndash292 2013

[73] J G Schellinger J A Pahang R N Johnson et al ldquoMelittin-graftedHPMA-oligolysine based copolymers for gene deliveryrdquoBiomaterials vol 34 no 9 pp 2318ndash2326 2013

[74] I M Neelov A Janaszewska B Klajnert et al ldquoMolecularproperties of lysine dendrimers and their interactions with a120573-peptides and neuronal cellsrdquo Current Medicinal Chemistry vol20 no 1 pp 134ndash143 2013

[75] K Li H Han K Zhu et al ldquoReal-time magnetic resonanceimaging visualization and quantitative assessment of diffusionin the cerebral extracellular space of C6 glioma-bearing ratsrdquoNeuroscience Letters vol 543 pp 84ndash89 2013

[76] L Albertazzi L Gherardini M Brondi et al ldquoIn vivo dis-tribution and toxicity of PAMAM dendrimers in the centralnervous system depend on their surface chemistryrdquo MolecularPharmaceutics vol 10 no 1 pp 249ndash260 2013

[77] A Kurihara and W M Pardridge ldquoImaging brain tumorsby targeting peptide radiopharmaceuticals through the blood-brain barrierrdquo Cancer Research vol 59 no 24 pp 6159ndash61631999

[78] A Kurihara and W M Pardridge ldquoA1205731minus40 peptide radiophar-maceuticals for brain amyloid imaging 111in chelation conju-gation to poly(ethylene glycol)-biotin linkers and autoradio-graphy with Alzheimerrsquos disease brain sectionsrdquo BioconjugateChemistry vol 11 no 3 pp 380ndash386 2000

[79] A Kurihara Y Deguchi and W M Pardridge ldquoEpidermalgrowth factor radiopharmaceuticals 111In chelation conjuga-tion to a blood-brain barrier delivery vector via a biotin-polyethylene linker pharacokinetics and in vivo imaging ofexperimental brain tumorsrdquoBioconjugate Chemistry vol 10 no3 pp 502ndash511 1999

[80] A Mukherjee U Pandey R Chakravarty H D Sarma andA Dash ldquoDevelopment of Single vial kits for preparation of(68)Ga-labelled peptides for PET imaging of neuroendocrinetumoursrdquo Molecular Imaging and Biology 2014

[81] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquo Molecular Pharmaceutics 2013

[82] P Laverman W J McBride R M Sharkey D M Goldenbergand O C Boerman ldquoAl(18) F labeling of peptides and proteinsrdquoJournal of Labelled Compounds amp Radiopharmaceuticals vol 57no 4 pp 219ndash223 2014

[83] T Reiner and BM Zeglis ldquoThe inverse electron demandDiels-Alder click reaction in radiochemistryrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 57 no 7 pp 285ndash290 2013

[84] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD An angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[85] B Barrios-Lopez M Raki and K Bergstrom ldquoRadiolabeledpeptides for Alzheimerrsquos diagnostic imaging mini reviewrdquoCurrent Radiopharmaceuticals vol 6 no 4 pp 181ndash191 2013

[86] X Lu L Zhao T Xue and H Zhang ldquoTechnetium-99m- Arg-Arg-Leu(g2) a modified peptide probe targeted to neovascular-ization in molecular tumor imagingrdquo Journal of BUON vol 18no 4 pp 1074ndash1081 2013

[87] Z Ortiz-Arzate C L Santos-Cuevas B E Ocampo-Garcıaet al ldquoKit preparation and biokinetics in women of 99mTc-EDDAHYNIC-E-[ c( RGDfK)]2 for breast cancer imagingrdquoNuclear Medicine Communications vol 35 no 4 pp 423ndash4322014

[88] S Maschauer R Haubner T Kuwert and O Prante ldquo(18 )F-Glyco-RGD peptides for PET imaging of integrin expressionefficient radiosynthesis by click chemistry and modulationof biodistribution by glycosylationrdquo Molecular Pharmaceutics2013

[89] MMichaelides S A AndersonMAnanth et al ldquoWhole-braincircuit dissection in free-moving animals reveals cell-specificmesocorticolimbic networksrdquo Journal of Clinical Investigationvol 123 no 12 pp 5342ndash5350 2013

[90] D Zeng Q Ouyang Z Cai X Q Xie and C J AndersonldquoNew cross-bridged cyclam derivative CB-TE1K1P an improvedbifunctional chelator for copper radionuclidesrdquo Chemical Com-munications vol 50 no 1 pp 43ndash45 2014

[91] K KairaHMurakamiM Endo et al ldquoBiological correlation of8F-FDGuptake on PET in pulmonary neuroendocrine tumorsrdquoAnticancer Res vol 33 no 10 pp 4219ndash28 2013

[92] Y Zhang and W M Pardridge ldquoConjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targetingsystem enables neuroprotection in regional brain ischemiafollowing intravenous injection of the neurotrophinrdquo BrainResearch vol 889 no 1-2 pp 49ndash56 2001

[93] W M Pardridge ldquoNeurotrophins neuroprotection and theblood-brain barrierrdquo Current Opinion in Investigational Drugsvol 3 no 12 pp 1753ndash1757 2002

[94] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[95] F Hefti ldquoPharmacology of neurotrophic factorsrdquo AnnualReview of Pharmacology and Toxicology vol 37 pp 239ndash2671997

[96] T Sakane and W M Pardridge ldquoCarboxyl-directed pegyla-tion of brain-derived neurotrophic factor markedly reducessystemic clearance with minimal loss of biologic activityrdquoPharmaceutical Research vol 14 no 8 pp 1085ndash1091 1997

[97] M Brines ldquoWhat evidence supports use of erythropoietin as anovel neurotherapeuticrdquo Oncology vol 16 supplement 10 no9 pp 79ndash89 2002

[98] S Genc T F Koroglu and K Genc ldquoErythropoietin as a novelneuroprotectantrdquo Restorative Neurology and Neuroscience vol22 no 2 pp 105ndash119 2004

[99] N L Jumbe ldquoErythropoietic agents as neurotherapeutic agentswhat barriers existrdquoOncology vol 16 no 9 supplement 10 pp91ndash107 2002

[100] I Ulusal R Tari G Ozturk et al ldquoDose-dependent ultra-structural and morphometric alterations after erythropoietintreatment in rat femoral artery vasospasm modelrdquo Acta Neu-rochirurgica vol 152 no 12 pp 2161ndash2166 2010

[101] T C Jackson J D Verrier and P M Kochanek ldquoAnthra-quinone-2-sulfonic acid (AQ2S) is a novel neurotherapeuticagentrdquo Cell Death amp Disease vol 4 no 1 article e451 2013

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

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ToxinsJournal of

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Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

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Medicinal ChemistryInternational Journal of

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BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

BioMed Research International 31

[102] A Sharma and H S Sharma ldquoMonoclonal antibodies as novelneurotherapeutic agents in CNS injury and repairrdquo Interna-tional Review of Neurobiology vol 102 pp 23ndash45 2012

[103] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[104] R K Stankovic R S Chung and M Penkowa ldquoMetalloth-ioneins I and II neuroprotective significance during CNSpathologyrdquo The International Journal of Biochemistry amp CellBiology vol 39 no 3 pp 484ndash489 2007

[105] L Bica P J Crouch R Cappai and A R White ldquoMetallo-complex activation of neuroprotective signalling pathways asa therapeutic treatment for Alzheimerrsquos diseaserdquo MolecularBioSystems vol 5 no 2 pp 134ndash142 2008

[106] R H Ring L E Schechter S K Leonard et al ldquoReceptorand behavioral pharmacology of WAY-267464 a non-peptideoxytocin receptor agonistrdquo Neuropharmacology vol 58 no 1pp 69ndash77 2010

[107] KN Fargo TDAlexander L Tanzer A Poletti andK J JonesldquoAndrogen regulates neuritin mRNA levels in an in vivo modelof steroid-enhanced peripheral nerve regenerationrdquo Journal ofNeurotrauma vol 25 no 5 pp 561ndash566 2008

[108] R L Frozza A Bernardi J B Hoppe et al ldquoNeuroprotectiveeffects of resveratrol against A120573 administration in rats areimproved by lipid-core nanocapsulesrdquoMolecular Neurobiologyvol 47 no 3 pp 1066ndash1080 2013

[109] A Sood and R Panchagnula ldquoPeroral route an opportunity forprotein and peptide drug deliveryrdquo Chemical Reviews vol 101no 11 pp 3275ndash3303 2001

[110] E K Hui R J Boado and W M Pardridge ldquoTumor necrosisfactor receptor-IgG fusion protein for targeted drug deliveryacross the human blood-brain barrierrdquo Molecular Pharmaceu-tics vol 6 no 5 pp 1536ndash1543 2009

[111] Y-S Kang K Voigt and U Bickel ldquoStability of the disulfidebond in an avidin-biotin linked chimeric peptide during in vivotranscytosis through brain endothelial cellsrdquo Journal of DrugTargeting vol 8 no 6 pp 425ndash434 2000

[112] Q Zhou E K Hui J Z Lu R J Boado and W M PardridgeldquoBrain penetrating IgG-erythropoietin fusion protein is neu-roprotective following intravenous treatment in Parkinsonrsquosdisease in the mouserdquo Brain Research vol 1382 pp 315ndash3202011

[113] KGuillemyn P Kleczkowska ANovoa et al ldquoIn vivo antinoci-ception of potent mu opioid agonist tetrapeptide analoguesand comparison with a compact opioid agonist neurokinin1 receptor antagonist chimerardquo Molecular Brain vol 5 no 1article 4 2012

[114] Q H Zhou J Z Lu E K Hui R J Boado andWM PardridgeldquoDelivery of a peptide radiopharmaceutical to brain with anIgG-avidin fusion proteinrdquo Bioconjugate Chemistry vol 22 no8 pp 1611ndash1618 2011

[115] I Brasnjevic HWM Steinbusch C Schmitz and PMartinez-Martinez ldquoDelivery of peptide and protein drugs over theblood-brain barrierrdquo Progress in Neurobiology vol 87 no 4 pp212ndash251 2009

[116] U Bickel T Yoshikawa and W M Pardridge ldquoDelivery of pep-tides and proteins through the blood-brain barrierrdquo AdvancedDrug Delivery Reviews vol 46 no 1ndash3 pp 247ndash279 2001

[117] G W M Vandermeulen and H Klok ldquoPeptideprotein hybridmaterials Enhanced control of structure and improved per-formance through conjugation of biological and synthetic

polymersrdquoMacromolecular Bioscience vol 4 no 4 pp 383ndash3982004

[118] N M Green ldquoAvidinrdquo Advances in Protein Chemistry vol 29pp 85ndash133 1975

[119] N McDannold N Vykhodtseva S Raymond F A Joleszand K Hynynen ldquoMRI-guided targeted blood-brain barrierdisruption with focused ultrasound histological findings inrabbitsrdquo Ultrasound in Medicine and Biology vol 31 no 11 pp1527ndash1537 2005

[120] K Hynynen N McDannold N A Sheikov F A Jolesz andN Vykhodtseva ldquoLocal and reversible blood-brain barrierdisruption by noninvasive focused ultrasound at frequenciessuitable for trans-skull sonicationsrdquo NeuroImage vol 24 no 1pp 12ndash20 2005

[121] K Hynynen N McDannold N Vykhodtseva et al ldquoFocal dis-ruption of the blood-brain barrier due to 260-kHz ultrasoundbursts a method for molecular imaging and targeted drugdeliveryrdquo Journal of Neurosurgery vol 105 no 3 pp 445ndash4542006

[122] H L Liu H W Yang M Y Hua and K Wei ldquoEnhanced ther-apeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruptionfor brain tumor treatment an overview of the current preclini-cal statusrdquo Neurosurgical focus vol 32 no 1 article e4 2012

[123] V P Torchilin ldquoStructure and design of polymeric surfactant-based drug delivery systemsrdquo Journal of Controlled Release vol73 no 2-3 pp 137ndash172 2001

[124] C H Fan C Y Ting H J Lin et al ldquoSPIO-conjugateddoxorubicin-loaded microbubbles for concurrent MRI andfocused-ultrasound enhanced brain-tumor drug deliveryrdquo Bio-materials vol 34 no 14 pp 3706ndash3715 2013

[125] R Alkins A Burgess M Ganguly et al ldquoFocused ultrasounddelivers targeted immune cells to metastatic brain tumorsrdquoCancer Research vol 73 no 6 pp 1892ndash1899 2013

[126] S Huang K Shao Y Kuang et al ldquoTumor targeting andmicroenvironment-responsive nanoparticles for gene deliveryrdquoBiomaterials vol 34 no 21 pp 5294ndash5302 2013

[127] M C Cochran J R Eisenbrey M C Soulen et al ldquoDispositionof ultrasound sensitive polymeric drug carrier in a rat hepato-cellular carcinoma modelrdquo Academic Radiology vol 18 no 11pp 1341ndash1348 2011

[128] A Mdzinarishvili V Sutariya P K Talasila W J Geldenhuysand P Sadana ldquoEngineering triiodothyronine (T3) nanoparticlefor use in ischemic brain strokerdquo Drug Delivery and Transla-tional Research vol 3 no 4 pp 309ndash317 2013

[129] A Iqbal I Ahmad M H Khalid M S Nawaz S H Ganand M A Kamal ldquoNanoneurotoxicity to nanoneuroprotectionusing biological and computational approachesrdquo Journal ofEnvironmental Science Health C Environmental Carcinogenesand Ecotoxicology Review vol 31 no 3 pp 256ndash284 2013

[130] Q Ye L Ye X Xu et al ldquoEpigallocatechin-3-gallate suppresses1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12cells via the SIRT1PGC-1120572 signaling pathwayrdquo BMC Comple-mentary andAlternativeMedicine vol 28 no 12 article 82 2012

[131] S Danjo Y Ishihara M Watanabe Y Nakamura and K ItohldquoPentylentetrazole-induced loss of blood-brain barrier integrityinvolves excess nitric oxide generation by neuronal nitric oxidesynthaserdquo Brain Research vol 1530 pp 44ndash53 2013

[132] N G Fisher J P Christiansen A Klibanov R P Taylor S Kauland J R Lindner ldquoInfluence of microbubble surface charge oncapillary transit andmyocardial contrast enhancementrdquo Journal

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

32 BioMed Research International

of the American College of Cardiology vol 40 no 4 pp 811ndash8192002

[133] C L Graff and G M Pollack ldquoP-glycoprotein attenuates brainuptake of substrates after nasal instillationrdquo PharmaceuticalResearch vol 20 no 8 pp 1225ndash1230 2003

[134] J M Yoffey ldquoPassage of fluid and other substances through thenasal mucosardquo The Journal of laryngology and otology vol 72no 5 pp 377ndash384 1958

[135] M Toborek M J Seelbach C S Rashid et al ldquoVoluntaryexercise protects against methamphetamine-induced oxidativestress in brain microvasculature and disruption of the bloodmdashbrain barrierrdquoMolecular Neurodegeneration vol 8 no 1 article22 2013

[136] E van der Pol A N Boing P Harrison A Sturk and RNieuwland ldquoClassification functions and clinical relevance ofextracellular vesiclesrdquo Pharmacological Reviews vol 64 no 3pp 676ndash705 2012

[137] A M S Hartz and B Bauer ldquoRegulation of ABC transportersat the blood-brain barrier new targets for CNS therapyrdquoMolecular Interventions vol 10 no 5 pp 293ndash304 2010

[138] Q Hu X Y Wang S Y Zhu L K Kang Y J Xiao and HY Zheng ldquoMeta analysis of contrast enhanced ultrasound forthe differentiation of benign andmalignant breast lesionsrdquoActaRadiologica 2014

[139] J G Swan J C Wilbur K L Moodie et al ldquoMicro bubblesare detected prior to large bubbles following decompressionrdquoJournal of Applied Physioliology vol 116 no 7 pp 790ndash7962014

[140] C Tremblay-Darveau RWilliams and PN Burns ldquoMeasuringabsolute blood pressure using microbubblesrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 775ndash787 2014

[141] Y H Chuang Y H Wang T K Chang C J Lin and PC Li ldquoAlbumin acts like transforming growth factor 1205731 inmicrobubble-based drug deliveryrdquo Ultrasound in Medcine andBiology vol 40 no 4 pp 765ndash774 2014

[142] T Muramoto R Shimoya K Yoshida and Y Watanabe ldquoEval-uation of the specific adsorption of biotinylated microbubblesusing a quartz crystal microbalancerdquo Ultrasound in Medicineand Biology vol 40 no 5 pp 1027ndash1033 2014

[143] M Jeon W Song E Huynh et al ldquoMethylene blue microbub-bles as amodel dual-modality contrast agent for ultrasound andactivatable photoacoustic imagingrdquo Journal of Biomed Opticsvol 19 no 1 Article ID 016005 2014

[144] M De Saint Victor C Crake C C Coussios and E StrideldquoProperties characteristics and applications of microbubblesfor sonothrombolysisrdquo Expert Opinion in Drug Delivery vol 11no 2 pp 187ndash209 2014

[145] A G Sorace M Korb J M Warram et al ldquoUltrasound-stimulated drug delivery for treatment of residual disease afterincomplete resection of head and neck cancerrdquo Ultrasound inMedicine and Biology vol 40 no 4 pp 755ndash764 2014

[146] J S Oh Y S Kwon K H Lee W Jeong S K Chung and KRhee ldquoDrug perfusion enhancement in tissue model by steadystreaming induced by oscillating microbubblesrdquo Computers inBiology and Medicine vol 44 pp 37ndash43 2013

[147] S L Gill H OrsquoNeill R J McCoy et al ldquoEnhanced deliveryof microRNA mimics to cardiomyocytes using ultrasoundresponsive microbubbles reverses hypertrophy in an in-vitromodelrdquo Technology Health Care vol 22 no 1 pp 37ndash51 2014

[148] W Tzu-Yin K E Wilson S Machtaler and J K Will-mann ldquoUltrasound and microbubble guided drug delivery

mechanistic understanding and clinical implicationsrdquo CurrentPharmaceutical Biotechnology vol 14 no 8 pp 743ndash752 2014

[149] N Hamano Y Negishi K Takatori et al ldquoCombinationof bubble liposomes and high-intensity focused ultrasound(HIFU) enhanced antitumor effect by tumor ablationrdquo Biologi-cal Pharmaceutical Bulletin vol 37 no 1 pp 174ndash177 2014

[150] S Stalmans E Wynendaele N Bracke et al ldquoBlood-brainbarrier transport of short proline-rich antimicrobial peptidesrdquoProtein Peptide Letters vol 21 no 4 pp 399ndash406 2013

[151] Z Tan R C Turner R L Leon et al ldquoBryostatin improvessurvival and reduces ischemic brain injury in aged rats afteracute ischemic strokerdquo Stroke vol 44 no 12 pp 3490ndash34972013

[152] P E Milbury and W Kalt ldquoXenobiotic metabolism and berryflavonoid transport across the blood-brain barrierrdquo Journal ofAgricultural and Food Chemistry vol 58 no 7 pp 3950ndash39562010

[153] K Kajimura Y Takagi NUeba et al ldquoProtective effect of Astra-gali Radix by oral administration against Japanese encephalitisvirus infection in micerdquo Biological amp Pharmaceutical Bulletinvol 19 no 9 pp 1166ndash1169 1996

[154] W F Guo and Z Y Zhou ldquoClinical and experimental study ofqing wen oral liquid in the treatment of viral infectious feverrdquoZhongguo Zhong Xi Yi Jie He Za Zhi vol 12 no 11 pp 656ndash6591992

[155] M Imer B Omay A Uzunkol et al ldquoEffect of magnesiumMK-801 and combination ofmagnesium andMK-801 on blood-brain barrier permeability and brain edema after experimentaltraumatic diffuse brain injuryrdquoNeurological research vol 31 no9 pp 977ndash981 2009

[156] S Shrot G Markel T Dushnitsky and A Krivoy ldquoThe possibleuse of oximes as antidotal therapy in organophosphate-inducedbrain damagerdquoNeuroToxicology vol 30 no 2 pp 167ndash173 2009

[157] Z Songjiang and W Lixiang ldquoAmyloid-beta associated withchitosan nano-carrier has favorable immunogenicity and per-meates the BBBrdquo AAPS PharmSciTech vol 10 no 3 pp 900ndash905 2009

[158] K M Sink X Leng J Williamson et al ldquoAngiotensin-converting enzyme inhibitors and cognitive decline in olderadults with hypertension results from the cardiovascular healthstudyrdquo Archives of Internal Medicine vol 169 no 13 pp 1195ndash1202 2009

[159] M C G Marcondes C Flynn S Huitron-Rezendiz D DWatry M Zandonatti and H S Fox ldquoEarly antiretroviraltreatment prevents the development of central nervous systemabnormalities in simian immunodeficiency virus-infected rhe-sus monkeysrdquo AIDS vol 23 no 10 pp 1187ndash1195 2009

[160] A Banerjee X Zhang K R Manda W A Banks and NErcal ldquoHIV proteins (gp120 and Tat) and methamphetaminein oxidative stress-induced damage in the brain Potential roleof the thiol antioxidant N-acetylcysteine amiderdquo Free RadicalBiology and Medicine vol 48 no 10 pp 1388ndash1398 2010

[161] P Couvreur G Barratt E Fattal P Legrand and C VauthierldquoNanocapsule technology a reviewrdquo Critical Reviews in Thera-peutic Drug Carrier Systems vol 19 no 2 pp 99ndash134 2002

[162] Y Liu J Tan A Thomas D Ou-Yang and V R MuzykantovldquoThe shape of things to come Importance of design in nan-otechnology for drug deliveryrdquo Therapeutic Delivery vol 3 no2 pp 181ndash194 2012

[163] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo International Journalof Pharmaceutics vol 379 no 2 pp 199ndash200 2009

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

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Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

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Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 33

[164] S V Vinogradov T K Bronich and A V Kabanov ldquoNanosizedcationic hydrogels for drug delivery preparation propertiesand interactions with cellsrdquo Advanced Drug Delivery Reviewsvol 54 no 1 pp 135ndash147 2002

[165] J K Sahni S Doggui J Ali S Baboota L Dao and CRamassamy ldquoNeurotherapeutic applications of nanoparticles inAlzheimerrsquos diseaserdquo Journal of Controlled Release vol 152 no2 pp 208ndash231 2011

[166] J Kreuter ldquoDrug delivery to the central nervous system bypolymeric nanoparticles what do we know rdquoAdvances in DrugDelivery Reviews vol 71 pp 2ndash14 2014

[167] C Vauthier C Dubernet E Fattal H Pinto-Alphandaryand P Couvreur ldquoPoly(alkylcyanoacrylates) as biodegradablematerials for biomedical applicationsrdquo Advanced Drug DeliveryReviews vol 55 no 4 pp 519ndash548 2003

[168] S Jain W T Yap and D J Irvine ldquoSynthesis of protein-loaded hydrogel particles in an aqueous two-phase systemfor coincident antigen and CpG oligonucleotide delivery toantigen-presenting cellsrdquo Biomacromolecules vol 6 no 5 pp2590ndash2600 2005

[169] M Uner ldquoPreparation characterization and physico-chemicalproperties of solid lipid nanoparticles (SLN) and nanostruc-tured lipid carriers (NLC) their benefits as colloidal drugcarrier systemsrdquo Pharmazie vol 61 no 5 pp 375ndash386 2006

[170] XWang D B Sykes and D S Miller ldquoConstitutive androstanereceptor-mediated up-regulation of ATP-driven xenobioticefflux transporters at the blood-brain barrierrdquo Molecular Phar-macology vol 78 no 3 pp 376ndash383 2010

[171] J Wang K Liu K C Sung C Tsai and J Fang ldquoLipid nano-particles with different oilfatty ester ratios as carriers ofbuprenorphine and its prodrugs for injectionrdquo European Jour-nal of Pharmaceutical Sciences vol 38 no 2 pp 138ndash146 2009

[172] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[173] F Yan Y Wang S He S Ku W Gu and L Ye ldquoTransferrin-conjugated fluorescein-loaded magnetic nanoparticles for tar-geted delivery across the blood-brain barrierrdquo Journal of MaterScience Mater Medicine vol 24 no 10 pp 2371ndash2379 2013

[174] S A Agnihotri N N Mallikarjuna and T M AminabhavildquoRecent advances on chitosan-based micro- and nanoparticlesin drug deliveryrdquo Journal of Controlled Release vol 100 no 1pp 5ndash28 2004

[175] A K Banga andYW Chien ldquoHydrogel-based iontotherapeuticdelivery devices for transdermal delivery of peptideproteindrugsrdquo Pharmaceutical Research vol 10 no 5 pp 697ndash7021993

[176] G Barratt D Betbeder and B Lebleu ldquoChallenges for nan-otechnology in delivery imaging Prefacerdquo Intentaional Journalof Pharmacy vol 379 no 2 pp 199ndash200 2009

[177] S Wohlfart A S Khalansky S Gelperina D Begley andJ Kreuter ldquoKinetics of transport of doxorubicin bound tonanoparticles across the blood-brain barrierrdquo Journal of Con-trolled Release vol 154 no 1 pp 103ndash107 2011

[178] C C Muller-Goymann ldquoPhysicochemical characterization ofcolloidal drug delivery systems such as reversemicelles vesiclesliquid crystals and nanoparticles for topical administrationrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol58 no 2 pp 343ndash356 2004

[179] M Malatesta M Giagnacovo M Costanzo et al ldquoDiamino-benzidine photoconversion is a suitable tool for tracking the

intracellular location of fluorescently labelled nanoparticles attransmission electron microscopyrdquo European Journal of Histo-chemistry vol 56 no 2 article e20 2012

[180] M A Rather R Sharma S Gupta S Ferosekhan V L Ramyaand S B Jadhao ldquoChitosan-nanoconjugated hormone nanopar-ticles for sustained surge of gonadotropins and enhancedreproductive output in female fishrdquo PLoS ONE vol 8 no 2Article ID e57094 2013

[181] R Mahjub F A Dorkoosh M Amini M R Khoshayand andM Rafiee-Tehrani ldquoPreparation statistical optimization andin vitro characterization of insulin nanoparticles composed ofquaternized aromatic derivatives of chitosanrdquo AAPS Pharm-SciTech vol 12 no 4 pp 1407ndash1419 2011

[182] C R Oliveira C M F Rezende M R Silva A P Pego OBorges andAMGoes ldquoAnew strategy based on smrhoproteinloaded chitosan nanoparticles as a candidate oral vaccineagainst schistosomiasisrdquo PLoS Neglected Tropical Diseases vol6 no 11 Article ID e1894 2012

[183] A Elsayed M Al-Remawi N Qinna A Farouk K A Al-SoursquoOd and A A Badwan ldquoChitosan-sodium lauryl sulfatenanoparticles as a carrier system for the in vivo delivery of oralinsulinrdquo AAPS PharmSciTech vol 12 no 3 pp 958ndash964 2011

[184] A Chaudhury and S Das ldquoRecent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin andother therapeutic agentsrdquoAAPS PharmSciTech vol 12 no 1 pp10ndash20 2011

[185] H Hosseinzadeh F Atyabi R Dinarvand and S N OstadldquoChitosan-Pluronic nanoparticles as oral delivery of anticancergemcitabine preparation and in vitro studyrdquo InternationalJournal of Nanomedicine vol 7 pp 1851ndash1863 2012

[186] M Alameh D de Jesus M Jean et al ldquoLow molecular weightchitosan nanoparticulate system at low NP ratio for nontoxicpolynucleotide deliveryrdquo International Journal of Nanomedicinevol 7 pp 1399ndash1414 2012

[187] I Kadiyala Y Loo K Roy J Rice and K W Leong ldquoTransportof chitosan-DNA nanoparticles in human intestinal M-cellmodel versus normal intestinal enterocytesrdquo European Journalof Pharmaceutical Sciences vol 39 no 1ndash3 pp 103ndash109 2010

[188] I Ozcan E Azizoglu T Senyigit M Ozyazıcı and O OzerldquoEnhanced dermal delivery of diflucortolone valerate usinglecithinchitosan nanoparticles in-vitro and in-vivo evalua-tionsrdquo International Journal of Nanomedicine vol 8 pp 461ndash475 2013

[189] A J Friedman J Phan D O Schairer et al ldquoAntimicrobial andanti-inflammatory activity of chitosan-alginate nanoparticles atargeted therapy for cutaneous pathogensrdquo Journal of Investiga-tive Dermatology vol 133 no 5 pp 1231ndash1239 2013

[190] S-F Shi J-F Jia X-K Guo et al ldquoBiocompatibility of chitosan-coated iron oxide nanoparticles with osteoblast cellsrdquo Interna-tional Journal of Nanomedicine vol 7 pp 5593ndash5602 2012

[191] C Chung K Chung Y Jeong and D H Kang ldquo5-aminolevulinic acid-incorporated nanoparticles of methoxypoly(ethylene glycol)-chitosan copolymer for photodynamictherapyrdquo International Journal of Nanomedicine vol 8 pp 809ndash819 2013

[192] K Bowman R Sarkar S Raut and KW Leong ldquoGene transferto hemophilia A mice via oral delivery of FVIII-chitosannanoparticlesrdquo Journal of Controlled Release vol 132 no 3 pp252ndash259 2008

[193] M Malhotra C Lane C Tomaro-Duchesneau S Saha and SPrakash ldquoA novel method for synthesizing PEGylated chitosan

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

34 BioMed Research International

nanoparticles strategy preparation and in vitro analysisrdquoInternational Journal of Nanomedicine vol 6 pp 485ndash494 2011

[194] L Zhang Z-L Zhao X-HWei and J-H Liu ldquoPreparation andin vitro and in vivo characterization of cyclosporin A-loadedPEGylated chitosan-modified lipid-based nanoparticlesrdquo Inter-national Journal of Nanomedicine vol 8 pp 601ndash610 2013

[195] T Yang D Nyiawung A Silber J Hao L Lai and S BaildquoComparative studies on chitosan and polylactic-co-glycolicacid incorporated nanoparticles of low molecular weight hep-arinrdquo AAPS PharmSciTech vol 13 no 4 pp 1309ndash1318 2013

[196] F Talaei E Azizi R Dinarvand and F Atyabi ldquoThiolatedchitosan nanoparticles as a delivery system for antisense ther-apy evaluation against EGFR in T47D breast cancer cellsrdquoInternational Journal of Nanomedicine vol 6 pp 1963ndash19752011

[197] T T Wager J L Liras S Mente and P Trapa ldquoStrategies tominimize CNS toxicity in vitro high-throughput assays andcomputational modelingrdquo Expert Opinion on Drug Metabolismand Toxicology vol 8 no 5 pp 531ndash542 2012

[198] J J Wang Z W Zeng R Z Xiao et al ldquoRecent advances ofchitosan nanoparticles as drug carriersrdquo International Journalof Nanomedicine vol 6 pp 765ndash774 2011

[199] J R Kanwar B Sriramoju and R K Kanwar ldquoNeurologicaldisorders and therapeutics targeted to surmount the blood-brain barrierrdquo International Journal of Nanomedicine vol 7 pp3259ndash3278 2012

[200] Y Hu W Qi F Han J Shao and J Gao ldquoToxicity evaluation ofbiodegradable chitosan nanoparticles using a zebrafish embryomodelrdquo International Journal of Nanomedicine vol 6 pp 3351ndash3359 2011

[201] E S Gil J Li H Xiao and T L Lowe ldquoQuaternary ammo-nium 120573-cyclodextrin nanoparticles for enhancing doxorubicinpermeability across the in vitro blood-brain barrierrdquo Biomacro-molecules vol 10 no 3 pp 505ndash516 2009

[202] X Qian Y H Cheng D D Mruk and C Y Cheng ldquoBreastcancer resistance protein (Bcrp) and the testismdashan unexpectedturn of eventsrdquo Asian Journal of Andrology vol 15 no 4 pp455ndash460 2013

[203] A Figueiras J M G Sarraguca A A C C Pais R A Carvalhoand J F Veiga ldquoThe role of l-arginine in inclusion complexesof omeprazole with cyclodextrinsrdquoAAPS PharmSciTech vol 11no 1 pp 233ndash240 2010

[204] J Zhang K Ellsworth and P X Ma ldquoHydrophobic pharma-ceuticals mediated self-assembly of beta-cyclodextrin contain-ing hydrophilic copolymers novel chemical responsive nano-vehicles for drug deliveryrdquo Journal of Controlled Release vol 145no 2 pp 116ndash123 2010

[205] KAAnsari P RVavia F Trotta andRCavalli ldquoCyclodextrin-based nanosponges for delivery of resveratrol in vitro charac-terisation stability cytotoxicity and permeation studyrdquo AAPSPharmSciTech vol 12 no 1 pp 279ndash286 2011

[206] M M Doile K A Fortunato I C Schmucker S K SchuckoM A S Silva and P O Rodrigues ldquoPhysicochemical prop-erties and dissolution studies of dexamethasone acetate-120573-cyclodextrin inclusion complexes produced by different meth-odsrdquo AAPS PharmSciTech vol 9 no 1 pp 314ndash321 2008

[207] C Bisson-Boutelliez S Fontanay C Finance and F Kedzi-erewicz ldquoPreparation and physicochemical characterization ofamoxicillin 120573-cyclodextrin complexesrdquo AAPS PharmSciTechvol 11 no 2 pp 574ndash581 2010

[208] K Songsurang J Pakdeebumrung N Praphairaksit and NMuangsin ldquoSustained release of amoxicillin from ethyl cel-lulose-coated amoxicillinchitosan-cyclodextrin-based tabletsrdquoAAPS PharmSciTech vol 12 no 1 pp 35ndash45 2011

[209] C Scarpignato ldquoPiroxicam-beta-cyclodextrin a GI safer pirox-icamrdquo Current Medicinal Chemistry vol 20 no 19 pp 2415ndash2437 2013

[210] H Yano and P Kleinebudde ldquoImprovement of dissolutionbehavior for poorly water-soluble drug by application ofcyclodextrin in extrusion process Comparison between meltextrusion and wet extrusionrdquo AAPS PharmSciTech vol 11 no2 pp 885ndash893 2010

[211] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[212] A S Jain A A Date R R S Pissurlenkar E C Coutinho andM S Nagarsenker ldquoSulfobutyl ether

7120573-cyclodextrin (SBE

7120573-

CD) carbamazepine complex Preparation characterizationmolecular modeling and evaluation of in vivo anti-epilepticactivityrdquo AAPS PharmSciTech vol 12 no 4 pp 1163ndash1175 2011

[213] I F Harrison and D T Dexter ldquoEpigenetic targeting of histonedeacetylase therapeutic potential in Parkinsonrsquos diseaserdquo Phar-macology andTherapeutics vol 140 no 1 pp 34ndash52 2013

[214] D S Miller ldquoRegulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrierrdquoTrends in Pharmacolog-ical Sciences vol 31 no 6 pp 246ndash254 2010

[215] A Chopra O-[11C ] Methyl Derivative of 67-Dimethoxy-2-(4-Methoxy-Biphenyl-4-yl- Methyl )-1234-Tetrahydro-Isoquino-line National Center for Biotechnology Information BethesdaMd USA 2012

[216] M Tachikawa Y Uchida and T Terasaki ldquoMulti-disciplinaryresearch approaches on the brain barrier transport system adynamic interfacerdquo Brain and Nerve vol 65 no 2 pp 121ndash1362013

[217] S Pilakka-Kanthikeel V S R Atluri V Sagar and M NairldquoTargeted brain derived neurotropic factors (BDNF) deliveryacross the blood-brain barrier for neuro-protection using mag-netic nano carriers an in-vitro studyrdquo PLoS ONE vol 8 no 4Article ID e62241 2013

[218] A Puri K Loomis B Smith et al ldquoLipid-based nanoparticles aspharmaceutical drug carriers from concepts to clinicrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 26 no 6 pp523ndash580 2009

[219] S Martins B Sarmento D C Ferreira and E B Souto ldquoLipid-based colloidal carriers for peptide and protein deliverymdashliposomes versus lipid nanoparticlesrdquo International Journal ofNanomedicine vol 2 no 4 pp 595ndash607 2007

[220] R Diab C Jaafar-Maalej H Fessi and P Maincent ldquoEngi-neered nanoparticulate drug delivery systems the next frontierfor oral administrationrdquo AAPS Journal vol 14 no 4 pp 688ndash702 2012

[221] S K Nitta and K Numata ldquoBiopolymer-based nanoparticlesfor druggene delivery and tissue engineeringrdquo InternationalJournal of Molecular Sciences vol 14 no 1 pp 1629ndash1654 2013

[222] D N Nguyen K P Mahon G Chikh et al ldquoLipid-derivednanoparticles for immunostimulatory RNA adjuvant deliveryrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 14 pp E797ndashE803 2012

[223] P Desai R R Patlolla and M Singh ldquoInteraction of nanopar-ticles and cell-penetrating peptides with skin for transdermal

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 35

drug deliveryrdquo Molecular Membrane Biology vol 27 no 7 pp247ndash259 2010

[224] O Le Bihan R Chevre S Mornet B Garnier B Pitard andO Lambert ldquoProbing the in vitro mechanism of action ofcationic lipidDNA lipoplexes at a nanometric scalerdquo NucleicAcids Research vol 39 no 4 pp 1595ndash1609 2011

[225] H Sah L A Thoma H R Desu E Sah and G C WoodldquoConcepts and practices used to develop functional PLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[226] A Yavlovich B Smith K Gupta R Blumenthal and A PurildquoLight-sensitive lipid-based nanoparticles for drug deliveryDesign principles and future considerations for biologicalapplicationsrdquo Molecular Membrane Biology vol 27 no 7 pp364ndash381 2010

[227] S Ramishetti and L Huang ldquoIntelligent design of multifunc-tional lipid-coated nanoparticle platforms for cancer therapyrdquoTherapeutic Delivery vol 3 no 12 pp 1429ndash1445 2012

[228] M T Nyunt C W Dicus Y Cui et al ldquoPhysico-chemicalcharacterization of polylipid nanoparticles for gene delivery tothe liverrdquo Bioconjugate Chemistry vol 20 no 11 pp 2047ndash20542009

[229] Q Huang G Zhong Y Zhang et al ldquoCyclen-based cationiclipids for highly efficient gene delivery towards tumor cellsrdquoPLoS ONE vol 6 no 8 Article ID e23134 2011

[230] X-X Zhang T J McIntosh and M W Grinstaff ldquoFunctionallipids and lipoplexes for improved gene deliveryrdquoBiochimie vol94 no 1 pp 42ndash58 2012

[231] F C Perez-Martınez J Guerra I Posadas and V CenaldquoBarriers to non-viral vector-mediated gene delivery in thenervous systemrdquo Pharmaceutical Research vol 28 no 8 pp1843ndash1858 2011

[232] T R Kuo D Y Wang Y C Chiu et al ldquoLayer-by-layer thinfilm of reduced graphene oxide and gold nanoparticles as aneffective sample plate in laser-induced desorptionionizationmass spectrometryrdquo Analytica Chimica Acta vol 809 pp 97ndash103 2014

[233] Y-C Kuo and C-C Wang ldquoCationic solid lipid nanoparticleswith cholesterol - mediated surface layer for transportingsaquinavir to the brainrdquo Biotechnology Progress vol 30 no 1pp 198ndash206 2014

[234] C Cornacchia I Cacciatore L Baldassarre A Mollica F Feli-ciani and F Pinnen ldquo25-Diketopiperazines as neuroprotectiveagentsrdquoMedicinal Chemistry vol 12 no 1 pp 2ndash12 2012

[235] I J Fidler ldquoThe role of the organ microenvironment in brainmetastasisrdquo Seminars in Cancer Biology vol 21 no 2 pp 107ndash112 2011

[236] A Prokop and J M Davidson ldquoNanovehicular intracellulardelivery systemsrdquo Journal of Pharmaceutical Sciences vol 97 no9 pp 3518ndash3590 2008

[237] M Roger A Clavreul M C Venier-Julienne C Passirani CMontero-Menei and P Menei ldquoThe potential of combinationsof drug-loaded nanoparticle systems and adult stem cells forglioma therapyrdquo Biomaterials vol 32 no 8 pp 2106ndash2116 2011

[238] E Miele G P Spinelli E D Fabrizio E Ferretti S Tomao andA Gulino ldquoNanoparticle-based delivery of small interferingRNA challenges for cancer therapyrdquo International Journal ofNanomedicine vol 7 pp 3637ndash3657 2012

[239] B Ozpolat A K Sood and G Lopez-Berestein ldquoLiposomalsiRNA nanocarriers for cancer therapyrdquo Advances in DrugDelivery Review vol 66 pp 110ndash116 2014

[240] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA and miRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[241] B Pulford N Reim A Bell et al ldquoLiposome-siRNA-peptidecomplexes cross the blood-brain barrier and significantlydecrease PrPC on neuronal cells and PrPRES in infected cellculturesrdquo PLoS ONE vol 5 no 6 Article ID e11085 2010

[242] S Ding and R Lu ldquoVirus-derived siRNAs and piRNAs inimmunity and pathogenesisrdquo Current Opinion in Virology vol1 no 6 pp 533ndash544 2011

[243] J L Li X Hou Y Liu et al ldquoNucleolin-targeting liposomesguided by aptamer AS1411 for the delivery of siRNA for thetreatment of malignant melanomasrdquo Biomaterials vol 35 no12 pp 3840ndash3850 2014

[244] P S Kowalski P J Zwiers H W Morselt et al ldquoAnti-VCAM-1 SAINT-O-Somes enable endothelial-specific deliveryof siRNA and downregulation of inflammatory genes in acti-vated endothelium in vivordquo Journal of Control Release vol 176Cpp 64ndash75 2014

[245] C Gon120591alves M Berchel M P Gosselin et al ldquoLipopoly-plexes comprising imidazoleimidazolium lipophosphorami-date histidinylated polyethyleneimine and siRNA as efficientformulation for siRNA transfectionrdquo International Journal ofPharmaceutics vol 460 no 1-2 pp 264ndash272 2013

[246] Z Dai M T Arevalo J Li and M Zeng ldquoAddition of poly(propylene glycol) to multiblock copolymer to optimize siRNAdeliveryrdquo Bioengineered vol 5 no 1 pp 30ndash37 2014

[247] JWang Z Lu B Z YeungMGWientjesD J Cole and J L-SAu ldquoTumor priming enhances siRNA delivery and transfectionin intraperitoneal tumorsrdquo Journal of Control Release vol 178pp 79ndash85 2014

[248] T Tsujiuchi A Natsume K Motomura et al ldquoPreclinicalevaluation of an O(6)-methylguanine-DNA methyltransferase-siRNAliposome complex administered by convection-enhanced delivery to rat and porcine brainsrdquo The AmericanJournal of Translational Research vol 6 no 2 pp 169ndash1782014

[249] S YWu andNAMcMillan ldquoLipidic systems for in vivo siRNAdeliveryrdquo The AAPS Journal vol 11 no 4 pp 639ndash652 2009

[250] G M Barratt ldquoTherapeutic applications of colloidal drugcarriersrdquo Pharmaceutical Science amp Technology Today vol 3 no5 pp 163ndash171 2000

[251] W N Charman H K Chan B C Finnin and S A CharmanldquoDrug delivery a key factor in realising the full therapeuticpotential of drugsrdquoDrugDevelopment Research vol 46 pp 316ndash327 1999

[252] J T Santini Jr A C Richards R Scheidt M J Cima andR Langer ldquoMicrochips as controlled drug-delivery devicesrdquoAngewandte Chemie International Edition vol 39 no 14 pp2396ndash2407 2000

[253] S Asthana P K Gupta M Chaurasia A Dube and M KChourasia ldquoPolymeric colloidal particulate systems intelligenttools for intracellular targeting of antileishmanial cargosrdquoExpert Opinion in Drug Delivery vol 10 no 12 pp 1633ndash16512013

[254] J Chen W T Dai Z M He et al ldquoFabrication and evaluationof curcumin-loaded nanoparticles based on solid lipid as anew type of colloidal drug delivery systemrdquo Indian Journal ofPharmaceutical Sciences vol 75 no 2 pp 178ndash184 2013

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

36 BioMed Research International

[255] R M Hathout ldquoUsing principal component analysis in study-ing the transdermal delivery of a lipophilic drug from softnano-colloidal carriers to develop a quantitative composition effectpermeability relationshiprdquo Pharmaceutical and DevelopmentTechnology vol 19 no 5 pp 598ndash604 2014

[256] M Jaganathan D Madhumitha and A Dhathathreyan ldquoPro-tein microcapsules preparation and applicationsrdquo Advances inColloid Interface Science vol 209 pp 1ndash7 2014

[257] E E Paoli E S Ingham H Zhang et al ldquoAccumulationinternalization and therapeutic efficacy of neuropilin-1-targetedliposomesrdquo Journal of Control Release vol 178 pp 108ndash117 2014

[258] C N Sanchez-Dominguez H L Gallardo-Blanco A ARodriguez-Rodriguez A V Vela-Gonzalez and M Sanchez-Dominguez ldquoNanoparticles vs cancer a multifuncional toolrdquoCurrent Topics in Medicinal Chemistry vol 14 no 5 pp 664ndash675 2014

[259] A Lopez-Noriega C L Hastings B Ozbakir et al ldquoHyperther-mia-induced drug delivery from thermosensitive liposomesencapsulated in an injectable hydrogel for local chemothera-pyeffectiveness of variable message signs on driving behaviorbased on a driving simulation experimentrdquoAdvances in Health-care Materials 2014

[260] K Ninomiya T Yamashita S Kawabata and N ShimizuldquoTargeted and ultrasound-triggered drug delivery using lipo-somes co-modified with cancer cell-targeting aptamers and athermosensitive polymerrdquoUltrasonic Sonochemistry vol 21 no4 pp 1482ndash1488 2014

[261] M S Kim D W Lee K Park et al ldquoTemperature-triggeredtumor-specific delivery of anticancer agents by cRGD-con-jugated thermosensitive liposomesrdquo Colloids and Surfaces BBiointerfaces vol 116 pp 17ndash25 2013

[262] N K Mittal H Bhattacharjee B Mandal P Balabathula L AThoma and G C Wood ldquoTargeted liposomal drug deliverysystems for the treatment of B cell malignanciesrdquo Journal ofDrug Targeting vol 22 no 5 pp 372ndash386 2014

[263] L Zhang D Y Cao J Wang et al ldquoPEG-coated irinotecancationic liposomes improve the therapeutic efficacy of breastcancer in animalsrdquoEuropean ReviewMedicinal PharmacologicalSciences vol 17 no 24 pp 3347ndash3361 2013

[264] B Sudhakar J N Varma and K VMurthy ldquoFormulation char-acterization and ex vivo studies of terbinafine HCl liposomesfor cutaneous deliveryrdquo Current Drug Delivery vol 11 no 4 pp521ndash530 2014

[265] K K Sarwa P K Suresh M Rudrapal and V K Verma ldquoPenetration of tamoxifen citrate loaded ethosomes and lipo-somes across human skin a comparative study with confocallaser scanning microscopyrdquo Current Drug Delivery vol 11 no3 pp 332ndash337 2014

[266] M Saffari F H Shirazi M A Oghabian and H R MoghimildquoPreparation and in-vitro evaluation of an antisense-containingcationic liposome against non-small cell lung cancer a com-parative preparation studyrdquo Iranian Journal of PharmaceuticalResearch vol 12 supplement pp 3ndash10 2013

[267] H Ding V Sagar M Agudelo et al ldquoEnhanced blood-brainbarrier transmigrationusing a novel transferrin embeddedfluo-rescent magneto-liposome nanoformulationrdquo Nanotechnologyvol 25 no 5 Article ID 055101 2014

[268] J Tang H Fu Q Kuang et al ldquoLiposomes co-modified withcholesterol anchored cleavable PEG and octaarginines fortumor targeted drug deliveryrdquo Journal of Drug Targeting vol 22no 4 pp 313ndash316 2014

[269] A D Tagalakis G D Kenny A S Bienemann et al ldquoPEGy-lation improves the receptor-mediated transfection efficiencyof peptide-targeted self-assembling anionic nanocomplexesrdquoJournal of Control Release vol 174 pp 177ndash187 2014

[270] A A Yaroslavov A V Sybachin O V Zaborova et al ldquoElectro-statically driven complexation of liposomes with a star-shapedpolyelectrolyte to low-toxicity multi-liposomal assembliesrdquoMacromolecular Bioscience vol 14 no 4 pp 491ndash495 2014

[271] P Vabbilisetty and X L Sun ldquoLiposome surface functionaliza-tion based on different anchoring lipids via Staudinger ligationrdquoOrganic Biomolecular Chemistry vol 12 pp 1237ndash1244 2014

[272] N Yamamoto and A Tamura ldquoDesigning cell-aggregatingpeptides without cytotoxicityrdquo Biomacromolecules vol 15 no2 pp 512ndash523 2014

[273] A Rosler G W M Vandermeulen and H A Klok ldquoAdvanceddrug delivery devices via self-assembly of amphiphilic blockcopolymersrdquoAdvanced Drug Delivery Reviews vol 53 no 1 pp95ndash108 2001

[274] MM Gaspar A F Penha A C Sousa et al Proceed 7th Lipos-omes Advances Progress in Drug and Vaccine Delivery Schoolof Pharmacy London UK 2005

[275] E M Cornford L D Braun W H Oldendorf and M A HillldquoComparison of lipid-mediated bloodndashbrain barrier penetrabil-ity in neonates and adultsrdquo American Journal of Physiology vol243 no 3 pp C161ndashC168 1982

[276] L Li J Hou X Liu et al ldquoNucleolin-targeting liposomes guidedby aptamer AS1411 for the delivery of siRNA for the treatment ofmalignant melanomasrdquo Biomaterials vol 35 no 12 pp 3840ndash3850 2014

[277] M El-Badry G Fetih and F Shakeel ldquoComparative topicaldelivery of antifungal drug croconazole using liposome andmicro-emulsion-based gel formulationsrdquoDrug Delivery vol 21no 1 pp 34ndash43 2014

[278] N Anton and T F Vandamme ldquoNano-emulsions and micro-emulsions clarifications of the critical differencesrdquo Pharmaceu-tical Research vol 28 no 5 pp 978ndash985 2011

[279] W He X Guo M Feng and N Mao ldquoIn vitro and in vivostudies on ocular vitamin A palmitate cationic liposomal in situgelsrdquo International Journal of Pharmaceutics vol 458 no 2 pp305ndash314 2013

[280] A S Abu Lila Y Uehara T Ishida andH Kiwada ldquoApplicationof polyglycerol coating to plasmidDNA lipoplex for the evasionof the accelerated blood clearance phenomenon in nucleic aciddeliveryrdquo Journal of Pharmaceutical Science vol 103 no 2 pp557ndash566 2013

[281] R Deng and J P Balthasar ldquoComparison of the effects ofantibody-coated liposomes IVIG and anti-RBC immunother-apy in a murine model of passive chronic immune thrombocy-topeniardquo Blood vol 109 no 6 pp 2470ndash2476 2007

[282] S R Sarker R Hokama and S Takeoka ldquoIntracellular deliveryof universal proteins using a lysine headgroup containingcationic liposomes deciphering the uptakemechanismrdquoMolec-ular Pharmacology vol 11 no 1 pp 164ndash174 2014

[283] G Weissmann A Brand and E C Franklin ldquoInteractionof immunoglobulins with liposomesrdquo The Journal of ClinicalInvestigation vol 53 no 2 pp 536ndash543 1974

[284] J Gao H Chen H Song et al ldquoAntibody-targeted immunoli-posomes for cancer treatmentrdquo Journal of Medicinal Chemistryvol 13 no 14 pp 2026ndash2035 2013

[285] N Okada T Yasuda T Tsumita and H Okada ldquoMembranesialoglycolipids regulate the activation of the alternative

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

BioMed Research International 37

complement pathway by liposomes containing trinitro-phenylaminocaproyldipalmitoylphosphatidylethanolaminerdquoImmunology vol 48 no 1 pp 129ndash140 1983

[286] R R Rando J Slama and F W Bangerter ldquoFunctional incor-poration of synthetic glycolipids into cellsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 77 no 5 pp 2510ndash2513 1980

[287] Y OhtsuboM Furukawa T Imagawa et al ldquoGrowth inhibitionof tumour cells by a liposome-encapsulated mycolic acid-containing glycolipid trehalose 236rsquo-trimycolaterdquo Immunol-ogy vol 74 no 3 pp 497ndash503 1991

[288] S Steinert E Lee G Tresset et al ldquoA fluorescent glycolipid-binding peptide probe traces cholesterol dependent microd-omain-derived trafficking pathwaysrdquo PLoS ONE vol 3 no 8Article ID e2933 2008

[289] S Biswas N S Dodwadkar R R Sawant and V P TorchilinldquoDevelopment of the novel PEG-PE-based polymer for thereversible attachment of specific ligands to liposomes synthesisand in vitro characterizationrdquo Bioconjugate Chemistry vol 22no 10 pp 2005ndash2013 2011

[290] Y Li T Su Y Zhang X Huang J Li and C Li ldquoLiposomalco-delivery of daptomycin and clarithromycin at an opti-mized ratio for treatment of methicillin-resistant Staphylococ-cus aureus infectionrdquo Drug Delivery 2014

[291] D S Pisal M P Kosloski and S V Balu-Iyer ldquoDelivery oftherapeutic proteinsrdquo Journal of Pharmaceutical Sciences vol99 no 6 pp 2557ndash2575 2010

[292] K Gradauer S Dunnhaupt C Vonach et al ldquoThiomer-coatedliposomes harbor permeation enhancing and efflux pumpinhibitory propertiesrdquo Journal of Controlled Release vol 165 no3 pp 207ndash215 2013

[293] R Srinivasan R E Marchant and A S Gupta ldquoIn vitro andin vivo platelet targeting by cyclic RGD-modified liposomesrdquoJournal of Biomedical Materials Research A vol 93 no 3 pp1004ndash1015 2010

[294] C-W Chen D-W Lu M-K Yeh C-Y Shiau and C-HChiang ldquoNovel RGD-lipid conjugate-modified liposomes forenhancing siRNA delivery in human retinal pigment epithelialcellsrdquo International Journal of Nanomedicine vol 6 pp 2567ndash2580 2011

[295] E Junquera and E Aicart ldquoCationic lipids as transfecting agentsof DNA in gene therapyrdquoCurrent Topics inMedicinal Chemistryvol 14 no 5 pp 649ndash663 2014

[296] M D Howard C F Greineder E D Hood and V R Muz-ykantov ldquoEndothelial targeting of liposomes encapsulatingSODcatalase mimetic EUK-134 alleviates acute pulmonaryinflammationrdquo Journal of Control Release vol 177 pp 34ndash412014

[297] R Haag ldquoSupramolecular drug-delivery systems based onpolymeric core-shell architecturesrdquo Angewandte ChemiemdashInternational Edition vol 43 no 3 pp 278ndash282 2004

[298] C Alvarez-Lorenzo and A Concheiro ldquoMolecularly imprintedpolymers for drug deliveryrdquo Journal of Chromatography BAnalytical Technologies in the Biomedical and Life Sciences vol804 no 1 pp 231ndash245 2004

[299] M Winterhalter C Hilty S M Bezrukov C Nardin W Meierand D Fournier ldquoControlling membrane permeability withbacterial porins application to encapsulated enzymesrdquo Talantavol 55 no 5 pp 965ndash971 2001

[300] J K Vasir K Tambwekar and S Garg ldquoBioadhesive micro-spheres as a controlled drug delivery systemrdquo InternationalJournal of Pharmaceutics vol 255 no 1-2 pp 13ndash32 2003

[301] M E Byrne K Park and N A Peppas ldquoMolecular imprintingwithin hydrogelsrdquo Advanced Drug Delivery Reviews vol 54 no1 pp 149ndash161 2002

[302] J W Park C C Benz and F J Martin ldquoFuture directionsof liposome- and immunoliposome-based cancer therapeuticsrdquoSeminars in Oncology vol 31 no 6 supplement 13 pp 196ndash2052004

[303] Y Bae S Fukushima A Harada and K Kataoka ldquoDesignof environment-sensitive supramolecular assemblies for intra-cellular drug delivery polymeric micelles that are responsiveto intracellular pH changerdquo Angewandte Chemie InternationalEdition vol 42 no 38 pp 4640ndash4643 2003

[304] N M Dand P B Patel A P Ayre and V J Kadam ldquoPolymericmicelles as a drug carrier for tumor targetingrdquo Chronicles ofYoung Scientists vol 4 no 2 pp 94ndash101 2013

[305] M Yokoyama ldquoPolymericmicelles as a new drug carrier systemand their required considerations for clinical trialsrdquo ExpertOpinion on Drug Delivery vol 7 no 2 pp 145ndash158 2010

[306] M Jones and J Leroux ldquoPolymeric micelles a new generationof colloidal drug carriersrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 48 no 2 pp 101ndash111 1999

[307] M Mazza R Notman J Anwar et al ldquoNanofiber-baseddelivery of therapeutic peptides to the brainrdquo ACS Nano vol7 no 2 pp 1016ndash1026 2013

[308] B Lee T Amano H Q Wang et al ldquoReactive oxygen speciesresponsive nanoprodrug to treat intracranial glioblastomardquoACS Nano vol 7 no 4 pp 3061ndash3077 2013

[309] D T Wiley P Webster A Gale and M E Davis ldquoTranscy-tosis and brain uptake of transferrin-containing nanoparticlesby tuning avidity to transferrin receptorrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 110 no 21 pp 8662ndash8667 2013

[310] AD Jeyasekharan Y Liu HHattori et al ldquoA cancer-associatedBRCA2 mutation reveals masked nuclear export signals con-trolling localizationrdquo Nature Structural amp Molecular Biologyvol 20 no 10 pp 1191ndash1198 2013

[311] A Jain A Jain A Gulbake S Shilpi P Hurkat and S K JainldquoPeptide and protein delivery using new drug delivery systemsrdquoCritical Reviews inTherapeutic Drug Carrier Systems vol 30 no4 pp 293ndash329 2013

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of