Nanoparticle-mediated drug delivery to high-grade...

Nanomedicine: Nanotechnology, Biology, and Medicine12 (2016) 1083–1093

Review Article

Nanoparticle-mediated drug delivery to high-grade gliomasGuido Frosina, PhD

Mutagenesis Unit, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

Received 7 December 2015; accepted 17 December 2015

nanomedjournal.com

Abstract

High grade gliomas (HGGs) are fatal brain tumors due to their infiltration capacity and the presence of resistant cell populations. Further,the brain is naturally protected from many exogenous molecules by the brain blood barrier (BBB), which limits or cancels passage ofcytotoxic drugs to the tumor sites. In order to cope with the latter problem, nanoparticle (NP)-based carriers are intensively investigated, dueto multiple possibilities to drive them across the BBB to the tumor sites and drop cytotoxic molecules there. The current status of research onNP for drug delivery to HGGs has been analyzed. The results indicate gold, lipids and proteins as three main materials featuring NPformulations for HGG treatment. Albeit specific drug targeting to HGG cells may have not been so far significantly improved, NP may helpdrugs crossing the BBB and enter the brain thus potentially fixing at least one part of the problem.

From the Clinical Editor: High grade gliomas (HGG) are very aggressive tumours and current therapy remains unsatisfactory. The advance innanomedicine has allowed the development of novel treatment modalities. In this review article, the authors outlined the current status in usingnanoparticle (NP)-based carriers for drug delivery to HGG. This should help readers to understand and develop ideas for further drug carrier designs.© 2016 Elsevier Inc. All rights reserved.

Key words: Brain blood barrier; Drug delivery; Glioma; Gold; Nanoparticle; Tumor targeting

Abbreviations: ACPP, activated cell-penetrating peptide; AFM, atomic force microscopy; AN, angiopeptin; ANP, NP modified with ACPP peptide; APE-1,apurinic endonuclease-1; AU, gold; AUC, area under the curve; AUNP, gold nanoparticles; AUNS, gold nanoshells; BAT, brain adjacent to tumor; BBB, bloodbrain barrier; BCl2L12, BCl2-like 12 protein; BER, DNA base excision repair; BSA, bovine serum albumin; BSAT1, brain-specific anion transporter; BTB,blood tumor barrier; CDDP, cis-dichlorodiamminoplatinum (II); CMAX, peak plasma concentration of drug; CNP, NP modified with CPP peptide; COX,cyclooxygenase; CPP, cell-penetrating peptide(s); CPT, camptothecin; c(RGDfK), cyclo-(Arg-Gly-Asp-D-Phe-Lys); c(RGDyK), cyclic (arginine-glycine-as-particacid-dtyrosine-lysine); CS, chitosan; CTX, chlorotoxin; CUR, curcumin; CX43, connexin 43; DGL, dendrigraft poly-l-lysines; DIR, 1,10-dioctade-cyl-3,3,30,30-tetramethylindo-tricarbocyanine iodide; DLS, dynamic light scattering; DOX, doxorubicin; DSC, differential scanning calorimetry; DSPE,1,2-distearoyl-sn-glycero-3-phosphoethanolamine; DTX, docetaxel; DTXPLAPEG, c(RGDyK)/docetaxel polylactic acidpolyethylene glycol; EGF, epidermalgrowth factor; F, folic acid; Fe3O4, ferric oxide; Fn14, fibroblast growth factor-inducible 14; FTIR, Fourier transform infrared spectroscopy; GIC, gliomainitiating cells; HA, hyaluronic acid; H/E, hematoxylin/eosin; HFC, high-resolution flow cytometry; HGG, high grade glioma; HIF2A, hypoxia-inducible factor2 alpha; IgG, immunoglobulin G; IHC, immunohistochemistry; IL, interleukin; ING, inhibitor of growth; IR, ionizing radiation; I.V, intravenous; LF, lactoferin;LIMK2, LIM Kinase 2; LNP, LIMK2 NOLS peptide; LRP, low density lipoprotein receptor-related protein; LUC, lucanthone; MAB, monoclonal antibody;MAN, p-aminophenyl-alpha-D-mannopyranoside; MANS, nanoshell loaded macrophages; MIR, microRNA; MO, monocyte; MRT, mean residence time;MTX, methotrexate; NA, neutravidin; NF, nuclear factor; NIR, near-infrared; NLC, nanostructured lipid carriers; NOLS, nucleolar translocation signalsequence; NP, nanoparticle(s); NPEG, non pegylated; NTA, NP tracking analysis; O-GNR, oxidized grapheme nanoribbons; PAMAM, polyamidoamine; PC4,phthalocyanine 4; PD, pharmacodynamics; PDT, photodynamic therapy; PEG, polyethyleneglycol or treatment with polyethyleneglycol or treated withpolyethyleneglycol; PENP, polyelectrolyte complex NP; PET, positron emission tomography; PHLIP, pH-sensitive low insertion peptide; PI, polydispersityindex; PK, pharmacokinetics; PLGA, poly (lactic-co-glycolic acid); PLN, polymer-lipid hybrid NP; PLP, porphyrin-based lipoprotein NP; PMAA,poly(methacrylic acid); PNIPAM, poly(N-isopropylacrylamide); PT, platinum; PTT, photothermal therapy; PTX, paclitaxel; RB, rhodamine B; RES,reticuloendothelial system; RF, radiofrequency; RGD, arginine-glycine-aspartic acid; SCID, severe combined immunodeficiency; SIRNA, small interferingRNA; SLN, solid lipid NP; SNA, spherical nucleic acid; T1/2 BETA, half-life of elimination phase; TEM, transmission electron microscopy; TF, transferrin;TMZ, temozolomide; TNFR, tumor necrosis factor receptor; TRPS, tunable resistive pulse sensing; TWEEN80, polysorbate 80; TW-MTX-TF-NP, NP coatedwith TWEEN80 and loaded with MTX and TF; UPA, urokinase plasminogen activator; VCR, vincristine; VEGF, vascular endothelial growth factor; VM,vasculogenic mimicry; WHO, World Health Organization.

Funding support from Compagnia San Paolo, Turin, Italy (Grant n. 2010.1944 and Project ”Terapie innovative per il glioblastoma” (PI: Prof. P. Malatesta)])is gratefully acknowledged.

Disclosure statement: The author declares no conflict of interest.E-mail address: [email protected].

http://dx.doi.org/10.1016/j.nano.2015.12.3751549-9634/© 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Frosina G, Nanoparticle-mediated drug delivery to high-grade gliomas. Nanomedicine: NBM 2016;12:1083-1093, http://dx.doi.org/10.1016/j.nano.2015.12.375

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Figure 1. Gold-formulated NP. (A) SNAs consist of densely functionalized and highly oriented oligonucleotides on the surface of NPs which can be inorganic(such as in gold NPs). In turn, oligonucleotides can be conjugated to cytotoxic drugs such as cisplatin or carboplatin for dual therapy. A schematic for thesynthesis of platinum (Pt) (IV) complex- terminated SNA is shown. From Barnaby et al10, with permission. (B)MIR-182-based SNAs penetrate GIC and reduceHGG growth in vivo. Left: MIR-182 or control (Co)-MIR-RNA duplexes were hybridized to citrate stabilized gold nanoparticles (AUNPs) via thiolgold bondand passivated with PEG-thiol. Right top: sequence of MIR-182 and Co-MIR duplexes. Right bottom left: bioluminescence imaging of xenograft tumors derivedfrom GIC, twelve days after intravenous treatment with Co-SNA or 182-SNA. Right bottom right: Kaplan–Meyer survival curves of severe combinedimmunodeficiency (SCID) mice carrying xenografted HGG which were treated with intravenously administered Co-SNA or 182-SNA. Median survival isindicated. From Kouri et al12, with permission. (C) AN-functionalized, gold-based NPs loaded with DOX. Top: schematic of the AN-PEG-DOX-AUNP.Bottom: schematic of the delivering procedure of AN-PEG-DOX-AUNP: LRP receptor could mediate AN-PEG-DOX-AUNP, penetrate through BBB and targetGIC, then DOX would be released at tumor site or in tumor cells and enter nuclei to induce tumor cell apoptosis. From Ruan et al14, with permission. (D)Targeting AUNPs with two or more receptor binding peptides to address intratumoral heterogeneity of HGG. AUNPs conjugated with peptides against both theEGF and TF receptors and loaded with the photosensitizer PC4 have been formulated and compared with monotargeted AUNPs for in vitro and in vivo studies.The (EGFpep+TFpep)-AUNP-PC4 with a particle size of ∼41 nm improved both specificity and worked synergistically to decrease time of maximalaccumulation in human GIC that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association andincreased cytotoxicity were achieved. In vivo studies showed accumulation of these agents in HGG tissues. From Dixit et al16, with permission. (E)Overview ofphotothermal therapy (PTT) via macrophage-mediated delivery of NPs into HGG. 1. Generation of AUNS. 2. Monocytes harvested from patients peripheralblood by leukapheresis. 3. Incubated ex vivo with AUNS for 24 h forming MANS. 4. MANS reinjected I.V. into patient. 5. MANS infiltration into resectioncavity wall and brain adjacent to tumor (BAT). 6. Intracavity NIR laser irradiation at λ = 810 nm causing cell death/remaining tumor ablation. Image of patientis from Theresa Winslow public domain National Cancer Institute, National Institute of Health. 2011. From Christie et al18, with permission.

1084 G. Frosina / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1083–1093

High grade gliomas (HGGs; WHO grades III and IV) are themost aggressive and lethal types of brain tumor typicallyrecurring within two centimeters of the resection cavity evenafter gross surgical removal followed by radio/chemotherapy.1,2

Tumor resistance to current therapies resides in cellularpopulations with high infiltrating capacity and frequent (but notinvariable) stem properties (glioma initiating cells; GICs).3

Chemotherapy of these tumors is especially problematic due to

their location: albeit the human brain comprises over 100 billioncapillaries with a total length of 400 miles, a total surface area of20 squaremeters and amedian inter-capillary distance of about 50micron, making it the best perfused organ in the body,4 mostlyavailable anti-cancer drugs are large hydrophobic molecules withrestricted permeation across the blood–brain barrier (BBB) andlimited access to brain tissues.5,6 Nanoparticles (NPs) withvarious shapes and ranging in size 1-1000 nm may be endowed

1085G. Frosina / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1083–1093

with biological stability and biocompatibility and by theircapacity to incorporate different molecules, may help to improvesolubility, prevent degradation and cross the BBB.7 Minimizingnon-specific binding of targeted NPs to normal tissues remainsyet a major and so far unsolved challenge in order to achievespecific drug delivery to scattered GIC.2 Albeit an essentiallyunlimited number of scaffolds and decorating molecules can becombined, the recently developedNPs for HGG treatment may bereconducted to gold, lipids and proteins as the three main classesof materials featuring their formulation.8,9

Gold

Spherical nucleic acids (SNAs) consist of densely function-alized and highly oriented oligonucleotides on the surface of anNP which can be made of solid gold10 (Figure 1, A). Thespherical architecture of the oligonucleotide shell may conferadvantages over traditional nucleic acid delivery methods,including entry into most cell types independent of transfectionagents and resistance to nuclease degradation. Further, SNA canpenetrate biological barriers, including the BBB and blood tumorbarrier (BTB) as well as the epidermis and have demonstratedsome efficacy in murine disease models in the absence ofsignificant adverse side effects.10 Starting with gold NP as acore, layer-by-layer degradable polymer coatings allow thedelivery of DNA or short interfering RNA (SIRNA) (or both)and upon the addition of multiple polyelectrolyte layers, the finalNP size may reach 200 nm in diameter. The hybrid gold/nucleicacid NPs are internalizable by HGG cells where they reach thecytoplasm and nucleus as shown by transmission electronmicroscopy (TEM) and exogenous gene expression. Deliverythrough this type of NPs may thus lead to both exogenous DNAexpression and SIRNA-mediated knockdown.11 Micro RNAs(MIR) which have been identified as regulators of apoptosis,growth and differentiation and whose expression level may becorrelated with HGG response to therapies, are one further typeof RNA deliverable by SNA12 (Figure 1, B). In particular,MIR-182 anti-HGG activity is exerted through the repression ofBCl2-like12 protein (BCl2L12), c-Met and hypoxia-induciblefactor 2 alpha (HIF2A) that ultimately results in decreasedexpansion and stemness of GIC in vitro and their sensitization totherapeutic agents. To evaluate the tumor-suppressive functionof MIR-182 in vivo, gold NPs have been covalently function-alized with mature MIR-182 duplexes (182-SNA) and intrave-nously (I.V.) administered to orthotopic HGG xenograft models.182-SNA penetrated the BBB/BTB and disseminated throughouttumor tissues, delaying disease progression and slightlyincreasing animal survival.12 Aptamers are nucleic acid speciesthat have been engineered through repeated rounds of in vitroselection to bind to various molecular targets such as smallmolecules, proteins and even cells and tissues.13 Aptamers areendowed with molecular recognition properties that rival thoseof antibodies with the additional advantages of being completelyengineered in a test tube, readily produced by chemical synthesisand eliciting little or no immunogenicity in therapeuticapplications. NPs loaded with cytotoxic drugs and conjugatedto aptamers specifically selected for in vivo HGG targeting are

currently under development.13 Figure 1, C shows a further goldNP-based delivery system, AN-PEG-DOX-AUNP which hasbeen functionalized with angiopep-2 (AN) and loaded with thecytotoxic anthracycline doxorubicin (DOX).14 AN is a specificligand of low density lipoprotein receptor-related protein-1(LRP1) which may mediate the NPs to penetrate the BBB andtarget GIC. In vivo, AN-PEG-DOX-AUNP distributed to HGGat a higher intensity than that of PEG-DOX-AUNP or free DOXand HGG-bearing mice treated with AN-PEG-DOX-AUNPdisplayed a limited increase of median survival.14 Targeteddelivery using epidermal growth factor (EGF) peptide-drivengold NP (EGFPEP-AU NP) is a further possibility. In vivostudies show that targeting with EGFPEP-AU NP loaded withthe photodynamic therapy (PDT) agent phthalocyanine 4 (PC4)improves accumulation of fluorescence of PC4 in HGG bygreater than threefold compared with untargeted AU NP.Tracking by PC4 fluorescence, it was demonstrated in vivothat EGFPEP-AU NP-PC4 impacted biodistribution of the NP bydecreasing the initial uptake by the reticuloendothelial system(RES) and by increasing the amount of AU NP circulating in theblood after I.V. injection. In vivo PDT with EGFPEP-AUNP-PC4 activated by light resulted in some delay of tumorgrowth when compared with EGFPEP-AU NP control mice.15 Ina following study, AU NPs loaded with PC4 were conjugatedwith peptides against both the EGF and transferrin (TF) receptors(Figure 1, D). In comparison to the monotargeted therapy, thedual (EGFPEP+TFPEP)-AUNP-PC4 with a particle size of~41 nm improved specificity and decreased time of maximalaccumulation in GIC and in vivo studies showed accumulation ofthese agents in HGG orthotopic regions.16 Gold NPs may alsoincrease the effectiveness of radiotherapy. This in part dependson the Auger effect, a physical phenomenon in which the fillingof an inner-shell vacancy of a gold atom is accompanied by theemission of a cytotoxic electron from the same atom. Since thiseffect is very localized, it is important to place the gold NPs on orin the cancer cells. The pH-sensitive, tumor-targeting agentLow-Insertion Peptide (PHLIP) has been used to that aim.17 Theconjugation of PHLIP to 1.4-nm gold NPs appeared to tether theNPs to GIC and increase cellular gold uptake as compared togold NPs without PHLIP, with the NPs distributed mostly on thecellular membranes. Despite a statistical significance with aP value of 0.015 was reported, gold NPs conjugated to PHLIPonly slightly (b25%) increased the effectiveness of ionizingradiation (IR) on GIC as compared with cells with AU aloneafter 1.5 Gy IR and no difference at all was observed after3.0 Gy.17 Finally, certain types of stem and immune cells,which have an innate ability to target and infiltrate HGG, may beutilized as vectors to deliver therapeutic NP (Figure 1, E). Forinstance, monocytes (MOs) and their differentiated formsmacrophages, have the advantage of carrying relatively largepayloads of therapeutic NPs, can be patient-derived in relativelylarge numbers and may be able to infiltrate HGG. In particular,MOs can cross the compromised BBB surrounding HGG andare known to actively migrate to hypoxic tumor regions. It hasbeen recently suggested that following near-infrared (NIR)exposure of HGG containing AU NP-loaded macrophages,sufficient hyperthermia may be generated to delay tumorgrowth.18


Lipids

Lipids are further basic materials for many types ofnanocarriers, which may be hollow (lipid shells) as in liposomesor solid (lipid dots) as in nanostructured lipid carriers (NLCs).

Lipid shells

Liposomes are small artificial vesicles of spherical shape thatcan be created from natural nontoxic lipids. A number of

techniques are available for the quality control of suchlipids-based NPs including NP tracking analysis (NTA), tunableresistive pulse sensing (TRPS), high-resolution flow cytometry(HFC), dynamic light scattering (DLS), TEM, differentialscanning calorimetry (DSC), Fourier transform infrared spec-troscopy (FTIR) and others.19 Using some of them, temozolo-mide (TMZ) loaded-liposomes relatively uniform in size with anarrow polydispersity index (PI) have been obtained by Gao andcoworkers.20 TMZ released slowly from these liposomes and

image of Figure�2


pharmacokinetics (PK) studies have shown that the half-life ofelimination (T1/2 BETA), mean residence time (MRT), peakplasma concentration (CMAX) and area under the curve (AUC)values of TMZ-liposomes were all greater than those of freeTMZ. The biodistribution in mice showed that TMZ-liposomesdecreased the accumulation of TMZ in heart and lung andincreased the drug concentration in brain after I.V. injection.20 A~40 nm-sized NP comprised of a cationic liposome encapsulat-ing TMZ has been described by Kim and coworkers as well.21

The surface of this liposome, designated as “SCL-TMZ”(referring to it being a liposome with a single chain antibodyfragment as a targeting moiety), was decorated with anti-TFreceptor single-chain antibody fragments to facilitate BBBcrossing. After systemic administration, SCL-TMZ prolongedto a limited extent the survival of mice bearing intracranialHGG.21 Free DOX is not currently used to treat HGG in partbecause the BBB limits its deposition into the brain and lethaltoxic effects occur when combined with IR. In order to overcomethese drawbacks, DOX has been encapsulated within liposomalcarriers and the therapeutic properties of these NP have beenevaluated using orthotopic HGG U87 xenografts.22 Encapsula-tion of DOX ensured a partially preferential drug deposition inthe tumor in comparison with the normal brain tissue that greatlydepended on the administration schedule. Under optimaldelivery conditions, potentiation of radiotherapy by liposomalDOX was observed in tumor-bearing animals suggesting that useof liposomal nanocarriers may be worth-investigating for thetargeted delivery of anthracyclines to HGG.22 The arginine–glycine–aspartic acid (RGD) sequence is the attachment site of anumber of proteins adhering to integrins present on the surface ofendothelial and HGG cells (e.g. the integrin alphavbeta3 which isprominently expressed on HGG but not normal brain cells).RGD peptides may thus promote both BBB crossing and HGGtargeting when conjugated to NP.23 Paclitaxel (PTX)-loadedliposomes modified with a multifunctional tandem peptideRRRRRRRRcyclicRGD-RRRRRRRRcyclicRGD [R8-C(RGD)(R8-C(RGD)-LIP] have been explored according tothis strategy.24 Pharmacodynamics (PD) studies suggested thatthe peptide-modified drug-loaded liposomes may achieve bothanti-vasculogenic mimicry (VM) and anti-GIC effects in vivo withno significant toxicity on the blood system or major organs.24

Figure 2, A shows a multicomponent, chain-like NP composed ofthree iron oxide nanospheres and one DOX-loaded liposome linkedchemically into a linear chain-like assembly that can penetrateHGG.25 In comparison to traditional small molecule drugs orspherical NP, this oblong-shaped, flexible nanochain particlepossessed increased ability to gain access to and accumulate atHGG sites. Vascular targeting of nanochains to the alphavbeta3

Figure 2. Lipid-formulated NPs. (A) Illustration of a nanochain particle and its therapethree iron oxide nanospheres and one drug-loaded liposome. Bottom left: TEM imageinvasive HGG via vascular targeting and RF-triggered drug release. From Peiris et al25,brain. Gross brain sections through tumor (left column) with corresponding multispesections (right column) at 30 min (top row), 2 h (middle row), and 4 h (bottom row) afteof liposome localization, are seen both within and surrounding the tumor at 30 min (cfluorescence appear to be peritumoral. By 4 h after intra-arterial delivery, much lower llimited areas of high intensity can be seen in regions surrounding the tumor. H/E, hematcharacterization of the core-shell nanostructure termed PLP. Left; schematic of PLP stru20 nm (the scales represent 100 and 20 nm for the whole view and magnified view, r

integrin receptor resulted in an 18-fold greater drug doseadministered to HGG than standard chemotherapy. By two hoursafter injection, when nanochains had exited the blood stream anddocked at vascular beds in the brain, the application of an externallow-power radiofrequency (RF) field could remotely trigger drugrelease. This effectwas produced bymechanically induced defects inthe liposomal membrane caused by the oscillation of the iron oxideportion of the nanochain. In comparison with free DOX, a 2.5-foldincrease in survival of the nanochain-treated animals followed byRFwas observed in mice bearing orthotopic HGG.25 A 188Re-labeledpegylated nanoliposome (188Re-liposome) has been developed forHGG treatment by Huang and coworkers.26 Tumor development invivo was monitored by using the reporter cell line F98luc andbioluminescent imaging. The maximum tolerated dose of188Re-liposome in Fischer344 rats was 333 MBq with higherequivalent doses in spleen and kidneys and lower doses in brain, redmarrow and thyroid. The progression of tumor growth in terms oftumor volume and/or tumor weight was slower for the188Re-liposome-treated group than the control group and thelifespan of HGG-bearing rats treated with 188Re-liposome wasslightly prolonged.26 The lipids used to form liposomes can becationic, anionic, neutral or a mixture thereof. Joshi and coworkershave compared liposomes with different electric charge for theircapacity to be effectively delivered to normal and HGG tissues afterintra-arterial injection.27 Liposomes were loaded with DilC18(5) dyewhose concentrations can be conveniently measured by lightabsorbance and fluorescence methods. After intra-arterial injection,higher uptake of cationic in comparison with anionic and neutralliposomes into brain parenchyma was observed by diffusereflectance spectroscopy. Postmortem multispectral fluorescenceimaging confirmed that liposomal cationic charge was associatedwith more efficient delivery to the brain and HGG tissues thanliposomes with negative charge or neutral (Figure 2, B).27 PEG isthe most commonly adopted strategy to prolong NP vascularcirculation by mitigating RES uptake. However, PEG also raisesissues of immunogenicity and targeting efficiencywhich spurs searchfor alternate, non-pegylated systems. A PEG-free, porphyrin-basedcore-shell structure termed PLP has been developed mimickingnature lipoproteins and integrating multiple imaging and therapeuticfunctionalities, including positron emission tomography (PET)imaging, NIR fluorescence imaging and PDT (Figure 2, C). PLPwas stable in the blood circulation resulting in favorable PK andbiodistributionwithout the need for PEG. Nanoshell dissociation wasobserved upon tumor accumulation, causing release of monomericporphyrins to generate fluorescence and photodynamic reactivity,thus providing an activatable mechanism for tumor-selective PDT.Labeling with 64Cu further allowed for noninvasive PET imaging ofPLP delivery and quantitative assessment of drug distribution. Using

utic effect on HGG. Top left: schematic of a linear nanochain particle composed ofof nanochain particles. Right: illustration of delivery of nanochain-based drug towith permission. (B) Time-course of cationic liposome retention in HGG-bearingctral fluorescence images (central column) and hematoxylin/eosin (H/E) stainedr intra-arterial liposome delivery, are shown.High levels of fluorescence, indicativeentral column, top) and after 2 h (central column, middle). The highest levels ofevels of fluorescence are seen within the tumor (central column, bottom), althoughoxylin and eosin; Tu, tumor. From Joshi et al27, with permission. (C) Scheme andcture Right: TEM showing a core-shell spherical structure of PLPwith size aroundespectively). From Cui et al28, with permission.

Figure 3. Protein-formulated NP. (A) Top: cRGD-BSA/KALA/DOX NP fabricated by self-assembly through electrostatic interaction between thecell-penetrating peptide KALA and cRGD-BSA, with cRGD as a tumor-targeting ligand. Under endosomal/lysosomal acidic conditions, the changes in theelectric charges of cRGD-BSA and KALA lead to the disassembly of the NP to accelerate intracellular drug release. Bottom: schematic illustration of theNP-mediated delivery of DOX to nuclei for HGG therapy. Cell uptake mediated by cRGD, internalization in endosomes, endolysosomal pH-triggereddisassembly to accelerate DOX release and accumulation of DOX in the cell nucleus are shown. From Chen et al34, with permission. (B) Left: NP drug deliverysystem developed by conjugating fibrin-binding peptide CREKA to PAMAM dendrimer, where PAMAM is used as drug carrier due to its small size and goodpenetration in tumor and CREKA is used to target the abundant fibrin in HGG for enhanced retention in tumor. Right: in vivo distribution ofCREKA-PEG-PAMAM-FITC/IR783 to orthotopic U87 HGG at 24 h after I.V. administration. Image was obtained by merging the following stains: blue, cellnuclei stained by DAPI. Green, FITC-labeled dendrimer NP. Red, HGG cells expressing red fluorescence protein. White dash lines, border of the HGG. FromZhao et al36, with permission. (C) Left: ex vivo images of brains harvested from HGG-bearing mice 24 h after I.V. administration of NP labeled with the NIRdye 1,10-dioctadecyl-3,3,30,30-tetramethylindo-tricarbocyanine iodide (DIR; left panel), CNP (central panel) and ANP (right panel). Right: survival curves ofHGG-bearing mice treated with four cycles of different PTX formulations at day 5, 8, 11 and 14 post GIC inoculation. The dose of PTX was 6 mg/kg. FromZhang et al37, with permission. (D)NP-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver TMZ toGIC through the mediation of the HGG-targeting peptide CTX. The NP, termed NP-TMZ-CTX, has a hydrodynamic size of b100 nm, exhibits stability in cellculture media for up to 2 weeks and can accommodate stable drug loading. From Fang et al38, with permission. (E) Treatment of HGG by CDDP-loaded NPconjugated with MABs against CX43 and BSAT1. Left: scheme of the synthesis of MAB-decorated nanogels. Right: survival curves of rats after treatment withCDDP encapsulated in nanocontainers. The groups of animals received the following preparations: DEXTROSE (the control group), dextrose (placebo); CDDP,free cisplatin; NG, CDDP-loaded, non-targeted nanogels; NG-MABCX43: CDDP-loaded nanogels with MAB against CX43; NG-MABBSAT1: CDDP-loadednanogels with MAB against BSAT1; NG-IgGm: CDDP-loaded nanogels with non-specific IgG. From Baklaushev et al39, with permission.


an orthotopic HGG model, PLP allowed delineation of tumor fromsurrounding healthy brain indicating a potential for intraoperativefluorescence-guided surgery and tumor-selective PDT.28

Lipid dots

Solid Lipid Nanoparticles (SLNs), the first generation of solidlipid carrier systems in nanometer range, were introduced as analternative to liposomes. SLNs are aqueous colloidal dispersionswhose matrix includes solid biodegradable lipids. SLNs exhibit

useful properties such as modulated release, fair bioavailabilityand drug incorporation, protection of chemically-labile mole-cules and cost effective excipients.29 Lactoferin (LF)-conjugateddocetaxel (DTX)-loaded SLNs for proficient delivery of DTX toHGG have been formulated.30 Cytotoxicity and uptake studiessuggested that conjugation of LF to SLN surface might increasedrug delivery to brain and specificity of HGG targeting.30

DTX-loaded SLNs have been further surface-modified with themannose derived ligand p-aminophenyl-alpha-D-mannopyranoside(MAN) using carbodiimide coupling. PK and brain distribution

image of Figure�3


studies suggested an increased inflow of DTX to brain thanks toconjugating MAN on surface of lipidic NPs.31 There are certainlimitations associated with SLNs yet, such as limited drug loadingcapacity and drug expulsion during storage,which can beminimizedby the next generation of solid lipids, NLCs. NLCs are lipid particleswith a controlled nanostructure that improves drug loading andretention during storage.29 SLNs andNLCs have been compared forco-delivery of vincristine (VCR) and TMZ aimed to exploit thesynergetic therapeutic action of the two drugs. Improved HGGinhibition in vivo was reported with NLC formulations as comparedto SLNs.32 Curcumin (CUR) is a yellow pigment-derived turmericused as a food addictive in Asia with antioxidant, anti-inflammatoryand anti-tumorigenic properties.33 CURmay exert anticancer effectsagainst different human tumors including breast, lung cancer andHGG by inhibiting the nuclear factor (NF)-kB and its downstreamgene products prostaglandin E2, cyclooxygenase (COX)-2 andinterleukin (IL)-8. CUR medical application has been limited yetbecause of its poor bioavailability, unsatisfying dispersity and rapidmetabolism in vivo. In order to mitigate those problems, NLCs fordelivery of CUR to HGG have been developed and theirphysiochemical characteristics determined by HPLC, TEM andphoton correlation spectrum analyses. In vivo, the NLC-CURimproved targeting of CUR to normal and HGG tissues with someinhibition of tumor growth.33

Proteins

As hinted at in the “Lipids” section, conjugation of nanosizeddrug carriers with proteins and peptides may be a strategy toenhance both BBB crossing and GIC targeting. A multifunctio-nalized NP albumin-based drug-delivery system with tumor-targeting, cell-penetrating and endolysosomal pH-responsiveproperties is shown in Figure 3, A. The NPs loaded with cytotoxicDOX and termed cRGD-BSA/KALA/DOX were fabricated byself-assembly through electrostatic interaction between thecell-penetrating peptide KALA and the tumor-targeting fusionligand cRGD-BSA. Under endosomal/lysosomal acidic condi-tions, the changes in the electric charges of cRGD-BSA andKALAled to the disassembly of the NPs and intracellular DOX release.cRGD-BSA/KALA/DOX NP showed some inhibitory effects inthe growth of alphavbeta3-integrin-overexpressed GIC.34 HGGshave extensive areas of necrosis and hypoxia, which result inincreased secretion of vascular endothelial growth factor (VEGF).In order to improve visualization of those tumor regions, NPs withferric oxide (Fe3O4) cores coated with BSA have been developed.The BSA was further conjugated with monoclonal antibodies(MABs) against VEGFwhich promoted binding toVEGF-positivetissues and improved MRI visualization of the intracranialtumors.35 The small size of NPs is critical for effective tumorpenetration and retention. Figure 3, B shows a small NP drugdelivery system which has been developed by conjugatingfibrin-binding peptide CREKA to polyamidoamine (PAMAM)dendrimer, where PAMAM is used as drug carrier due to its smallsize and good tumor penetration and CREKA is used to target theabundant HGG fibrin component.36 In vivo fluorescence imagingof HGG-bearing mice, ex vivo brain imaging and fluorescenceimaging of frozen slices revealed that the CREKA-modified

PAMAM achieved higher accumulation and deeper penetration inHGG tissue than the unmodified carrier.36 Multi-targeting NPs(ANPs) modified with urokinase plasminogen activator (UPA)-activated cell-penetrating peptide (ACPP) for the treatment ofHGG have been developed by Zhang and coworkers37 (Figure 3,C). The ACPP decoration contributed to NP accumulation at theHGG site and ANPs could co-localize with both HGGparenchymal and stromal cells including neo-vascular cells andtumor-associated macrophages. ACPP-mediated targeting ofpaclitaxel (PTX) slightly prolonged the survival time ofHGG-bearing mice.37 Figure 3, D shows an NP-based carrierthat can protect TMZ from rapid degradation in physiologicalsolutions and deliver it to GIC through the mediation of thetumor-targeting peptide chlorotoxin (CTX).38 CTX is a 36-aminoacid peptide found in the venom of the deathstalker scorpion(Leiurus quinquestriatus) that may preferentially bind to GIC. TheNP system NP-TMZ-CTX was comprised of a chitosan (CS) coreloaded with TMZ and a shell containing CTX attached toneutravidin (NA). It had a hydrodynamic size of b100 nm,exhibited stability in cell culture media and could accommodatesufficient drug amounts. TMZ showed higher stability atphysiological pH when bound to these NPs with a half-life7-fold greater than that of the free TMZ molecule.38 Thepreferential expression of membrane protein connexin 43(CX43) and brain-specific anion transporter (BSAT1) in thetumor and peritumoral area has been exploited as well for targeteddelivery of cis-dichlorodiamminoplatinum (II) (CDDP). Figure 3,E shows the design of CDDP-loaded PEG-poly(methacrylic acid)(PEG-PMAA) copolymer nanogels conjugated with MAB toCX43 or BSAT1 for the treatment of orthotopic HGG. Themediansurvivals of rats treated with the CDDP-loaded, targeted nanogelsconjugated with MAB against CX43 and BSAT1 were 42 and39 days versus 31 days in the free CDDP control group.39 A newgene vector termedDGL-PEG-LNP has been constructed based ondendrigraft poly-l-lysines (DGL) and PEG and conjugated with acell-penetrating peptide, the nucleolar translocation signal (NOLS)sequence of the LIM Kinase 2 (LIMK2) protein (LIMK2 NOLSpeptide, LNP). Plasmid DNA encoding the inhibitor of growth(ING) 4 was applied as the therapeutic gene. The conjugation ofLNP improved the BBB-crossing efficiency, cellular uptake andgene expression within HGG cells. Mechanistic studies suggestedthe involvement of caveolae-mediated endocytosis and macro-pinocytosis in the cellular uptake of LNP-modified NP. LNP-modifiedNPmediated apoptosis at the tumor site and increased themedian survival time of HGG-bearing mice of nine days (from38 days without to 47 days with LNP conjugation).40 Amodification of the cRGD peptide, cyclic arginineglycineasparticaciddtyrosinelysine [c(RGDyK)], displays improved bindingaffinity to integrin alphavbeta3 receptors that are overexpressedin HGG and has been employed as a novel approach to targetHGG. c(RGDyK)/DTX polylactic acid polyethylene glycol(DTXPLAPEG) micelles were prepared and characterized. UponI.V. administration, c(RGDyK)/DTXPLAPEG showed internali-zation in HGG tissues and reduced the growth of tumors in U87HGG tumor xenografts.41 Fibroblast growth factor-inducible 14(Fn14) is a member of the tumor necrosis factor receptor (TNFR)superfamily that is minimally expressed in normal human brain buthighly expressed in some HGG.42 In particular, elevated Fn14

Figure 4. Other formulations. (A) Schematic representations of the formulation and chemical structure of PLGA NP coated with TWEEN 80 and loaded withMTX-TF conjugates (TW-MTX-TF-NP). From Jain et al44, with permission. (B) Drug-encapsulated aerosolized microspheres (so-called “DREAM BIG”therapy). A rat brain sprayed with RB-PLGA microspheres suspended in poly(N-isopropylacrylamide) (PNIPAM) solution imaged with (left) bright field and(right) fluorescence microscopy. Scale bar is 5000 micron. From Floyd et al45, with permission. (C)Hypothetical scheme of PENP-mediated drug delivery. Theformation of electrostatic complexes between negatively-charged HA and positively-charged CS and subsequent CD44-mediated drug delivery by PENP, isshown. From Yang et al47, with permission. (D) Top left. Representative atomic force microscope (AFM) image of oxidized graphene nanoribbons (O-GNRs)showing two completely unzipped O-GNRs ~500 nm in length. Top right. Representative low resolution TEM image of O-GNRs showing multiple unzippedO-GNRs. Bottom. Schematic showing the unzipping of multi-walled tubes to form O-GNRs, coating with PEG-DSPE to form O-GNR-PEG-DSPE and loadingwith LUC to form O-GNR-PEG-DSPE-LUC. From Chowdhury et al48, with permission.


mRNA and protein expression has been detected in the invasiverim of HGG, suggesting the opportunity to target these cells withFn14-directed therapeutics. NPs decorated withMABs that bind toFn14 were shown capable to diffuse within brain tissue and beinternalized by Fn14-positive HGG cells. When administeredintracranially, Fn14-targeting NPs displayed improved tumor cellco-localization in mice bearing human HGG xenografts incomparison to non-targeted NP.42

Other formulations

The ability of systemically administered poly-lactic-co-glycolicacid (PLGA)NP to deliver hydrophobic drugs to intracranial HGGhas been described.43 The hydrophobic payload encapsulatedwithin PLGA NP accumulated at remarkably 10× higher levels intumor compared to healthy brain. Tolerability of the chemother-apeutic camptothecin (CPT) was improved by encapsulation,enabling safe administration of up to 20 mg/kg drug whenencapsulated within NP. Immunohistochemistry (IHC) staining for

gamma-H2AX, a marker for double-strand breaks, demonstratedhigher levels of drug activity in tumors treated with CPT-loaded NPcompared to free CPT. CPT-loaded NP could slow the growth ofintracranial GL261 tumors in immune competent C57 albino mice,providing a slight (4.5 days) but once again statistically highlysignificant (P =0.0182) survival benefit compared to mice receivingfree CPT.43 Permeation of bioactive molecules across BBB has beenenhanced through PLGA NP coated with polysorbate 80 (TWEEN80) and loaded with methotrexate-transferrin (MTX-TF) conjugates(TW-MTX-TF-NP)44 (Figure 4, A). TWEEN 80 allowed fortrans-BBB migration through endocytosis and inhibition of P-GPefflux pumppresent in brainwhile the over-expression ofTF receptorson GIC surface allowed targeted delivery of NPs conjugated withMTX-TF by receptor-mediated endocytosis. The NP PK wasdetermined by I.V. administration of FITC-labeled, drug-loaded NPto albino rats and a limited anti-tumor efficacy was observed inorthotopic HGG-bearing rats.44 Drug-encapsulated aerosolizedmicrospheres have been proposed as a biodegradable targeted therapyfor HGG (so-called “DREAMBIG” therapy). DREAMBIG therapy

image of Figure�4


delivers chemotherapeutics via a bioadhesive, biodegradable spraydirectly to the brain surgical site after tumor excision.45 Rhodamine B(RB)-encapsulatedPLGAand immunoglobulinG (IgG)-encapsulatedpoly(lactic acid)microsphereswere formulated and characterized. Theencapsulation efficiency of RB and IgG and the release kinetics of themodel drugs from the microspheres were determined and theaerosolized application onto brain tissue ex-vivo allowed the partiallyconformed adhesion of the RB-encapsulated PLGA microspheres tothe convoluted brain surface45 (Figure 4, B). In vivo delivery studiesto the surgical site with analysis of animal survival are required todetermine the actual efficacy of DREAMBIG therapy. Polymer-lipidhybrid nanoparticles (PLNs) represent an additional class of NPsmergedwith the benefits of two aforementioned types: polymericNPsand liposomes.46 It consists of three layers: a biodegradable PLGAcore for the efficient loading of poorly water-soluble therapeutics; alipid monolayer surrounding the core and a lipid-PEG outer corona.The lipid monolayer provides stability and reduces outward diffusionof the encapsulated drug. The pegylated lipids layer increases the NPstability in in vivo circulation and also provides means to attachligands that can be exploited to specifically bind to the receptors on theendothelial and diseased cells and get internalized via receptor-mediated endocytosis. In particular, specialized transport systems existfor the transport of folic acid (F) within the brain capillary endothelialwall in vivowhich ensures adequate supply of this vitamin to the brain.F-decorated PLNs encapsulating cyclo-[Arg-Gly-Asp-D-Phe-Lys](cRGDfK)-modified PTX (PTXR-FPLN) have been developed forHGG treatment.46 The prepared PLNs bypassed the BBB and thentargeted integrin-rich GIC, extending the median survival oforthotopic HGG-bearing mice.46 The anionic, nonsulfated glycos-aminoglycan hyaluronic acid (HA) is a chief component of theextracellular matrix in different tissues of connective, epithelial, andneural origin.47 It may contribute to tumor cell proliferation andmigration and is unique among glycosaminoglycans in that it isnonsulfated, forms in the plasma membrane instead of the Golgiapparatus and can be very large, with molecular weights oftenreaching the millions. CS is a linear polysaccharide composed ofrandomly distributed β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine whose abundant amine groups can be utilized forcovalent attachment of drugs, imaging agents and targeting moieties.Figure 4, C shows the potential of polyelectrolyte complexnanoparticles (PENPs) based onHA/CS as carriers forwater-insolubleCUR. PENP composition was affected by the order of addition, massratios, pH, ionic strength and initial concentrations of the HA/CS.CUR was successfully encapsulated into the PENPs and drug releasestudies revealed an initial burst release followed by a sustained pattern.The uptake of CUR-PENP by C6 HGG cells was found to begoverned by different mechanisms including macropinocytosis,clathrin-, caveolae- and CD44-mediated endocytosis.47 Graphene isa crystalline allotrope of carbon with 2-dimensional properties. Itscarbon atoms are densely packed in a regular atomic-scale hexagonalpattern. Graphene is obtained by treatment of graphite with a stronglyacidic solution and subsequent oxidization and exfoliation to obtaincircles of graphene with carboxyl groups at the edges. Figure 4, Dshows oxidized graphene nanoplatelets coated with the amphiphilicpolymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEGwhich have been shown capable to load aromatic molecules andpermit cell specific drug delivery.48 The anti-tumor drug Lucanthone(LUC) inhibits the DNA base excision repair (BER) enzyme APE-1

(apurinic endonuclease-1) that may act as a resistance mechanism toTMZ chemotherapy in HGG.3 Lucanthone was loaded onto PEG-DSPE-coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE)using a simple non-covalent method. Its uptake was higher in theHGG cell line U251 as compared to the rat glial progenitor cell lineCG-4 and consistently, Luc-O-GNR-PEG-DSPE was more toxic toU251 than to CG-4 cells. This differential uptake effect might beexploited for preferential Luc delivery to GIC, while reducingnonspecific cytotoxicity to the surrounding healthy neural stem cellsreservoir.48 Graphene remains yet an experimental material whosetoxicity on human health is worrisome, in particular for its long-termeffects.49 It has been suggested that graphite-derived NPsmay exhibithigher toxicity on HGG than on hepatoma cells suggesting that theseNPs could be a potentially useful tool for specific therapeutics deliveryto brain tumors.50 Interestingly, NPs prepared from diamond, anadditional allotropic state of carbon, are practically nontoxic to bothHGGandhepatoma cells although theymaypose other kinds of issues(http://www.rsc.org/chemistryworld/News/2008/April/28040802.asp).

Conclusions

In order to be effective, drugs for HGG must enter the brainand specifically kill the tumor cells. The latter problem at themoment does not seem significantly coped with, using NPs.Targeting GIC by NPs decorated with tumor-targeting molecules[e.g. peptides binding to EGF receptors or fibrin, MAB to VEGFor FN14, CTX, PHLIP and c(RGD) peptides] has so far led tolimited-only (albeit often statistically significant) survivalimprovements as compared to targeting procedures not involvingNPs. Further, most in vivo studies have been performed on HGGanimal tumor models developed from established, rather thanprimary, cell lines such as U87, which unfaithfully reproduce thehuman tumor neovascularization and infiltration properties, thusweakening the possible relevance of results to humans.51

However, mainly due to their size and further facilitated byconjugation with endothelial cells-penetrating molecules (TFreceptor antibodies, AN, ACPP, CX43, BSAT1, KALA, LNP),NPs have shown promise as carriers of drugs through the BBB.This may represent a most important advance for developmentof more effective therapies for HGG and deserves furtherresearch efforts.

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