R Subbiah Et Al_Curr Med Chem

Current Medicinal Chemistry, 2010, 17, 4559-4577 4559

0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

Nanoparticles: Functionalization and Multifunctional Applications in

Biomedical Sciences

R. Subbiah, M. Veerapandian and K.S. Yun*

College of Bionanotechnology, Kyungwon University, South Korea

Abstract: Rapid innovations in nanomedicine have increased the likelihood that engineered nanomaterials will eventually come in contact with humans and the environment. The advent of nanotechnology has created strong interest in many fields such as biomedical sciences and engineering field. Central to any significant advances in nanomaterial based appli-cations will be the development of functionalized nanoparticles, which are believed to hold promise for use in fields such as pharmaceutical and biomedical sciences. Early clinical results have suggested that functionalization of nanoparticles with specific recognition chemical moieties indeed yields multifunctional nanoparticles with enhanced efficacy, while si-multaneously reducing side effects, due to properties such as targeted localization in tumors and active cellular uptake. A prerequisite for advancing this area of research is the development of chemical methods to conjugate chemical moieties onto nanoparticles in a reliable manner. In recent years a variety of chemical methods have been developed to synthesize functionalized nanoparticles specifically for drug delivery, cancer therapy, diagnostics, tissue engineering and molecular biology, and the structure-function relationship of these functionalized nanoparticles has been extensively examined. With the growing understanding of methods to functionalize nanoparticles and the continued efforts of creative scientists to ad-vance this technology, it is likely that functionalized nanoparticles will become an important tool in the above mentioned areas. Therefore, the aim of this review is to provide basic information on nanoparticles, describe previously developed methods to functionalize nanoparticles and discuss their potential applications in biomedical sciences. The information provided in this review is important in regards to the safe and widespread use of functionalized nanoparticles particularly in the biomedicine field.

Keywords: Asymmetric group, Bio-functionalization, Cancer therapy, Drug delivery, Functionalized nanoparticles, Post-polymerization, Thiol group, Tissue engineering.

1. INTRODUCTION

Nanotechnology is the study of functional systems at the molecular level and it is one of the fast growing areas of re-search in many scientific disciplines. Work in the nanotech-nology field began as early as 1959. The theoretical capabil-ity of building things with atomic precision was initially en-visioned by the physicist Richard Feynman who stated that “There is plenty of room at the bottom” [1]. Nanoparticles (NPs), which range in size from 1-100 nm, are attractive multifunctional materials due to their unique size, chemical and physical properties. Several advances have been made in the past years in regards to the synthesis of NPs, which has opened up the door to numerous original applications in many different fields including nanomedicine, biomedical sciences and engineering. The literature on NPs is already very dense and well investigated starting from metal NPs to polymer NPs among which gold (Au), silver (Ag), silica (Si), PEG, PLGA, PCL (see the summary of abbreviations in Ta-ble 1) have been extensively studied and are already found in various applications such as catalysis, chemical sensing, bio-labeling, photonics and nanocarrier for drug and bio-molecules delivery [2-7]. Potential biomedical applications of NPs have increased in the last decades due to their resis-tance to oxidation, easy synthesis, and optical properties and if appropriate ligands functionalization is used they can be highly tolerated by organs [8]. Metal NPs are good vehicles for tracers and therapeutic agents and can be easily function-alized. In addition, polymeric NPs are biocompatible and can serve as active targeting nanocarriers. Despite the many

*Address correspondence to this author at the Bionanotechnology, Kyung-

won University, Gyeonggi-do 461-701, South Korea; Tel: +82-31-750-

8753; Fax: +82-31-750-8819; E-mail: [email protected]

advantages of NPs, they also have some drawbacks including the lack of surface properties. In addition, NPs can interact with host media, substrates and/or other individual species such as molecules and other particles, all of which could limit their use in specific applications. However, these draw-backs can be eliminated by functionalizing the NPs with certain chemical moieties. One of the beneficial conse-quences of functionalizing NPs is that the desired properties can be controlled in a predictable manner to fit the specific applications [9-11]. The processes used to generate, manipu-late and deploy functionalized nanoparticles (FNPs) provides excitingly new possibilities for the development of new mul-tifunctional tools for biomedical and nanotechnological ap-plications. Furthermore, magnetite NPs have received sig-nificant attention in diagnostic applications due to their mag-netic properties, high surface area and the possibilities of surface functionalization, which show a great versatility in specialized fields such as medical diagnosis (MRI - magnetic resonance imaging), therapy and targeted drug delivery [12-17]. Indeed, functionalization has been used to conjugate drug molecules, polymers and organic groups to NPs. In addition, functionalization has also been shown to protect NPs against agglomeration [18, 19] and render them com-patible in other phases [20]. Functionalization also improves the physical, chemical and mechanical properties of NPs, which are synergetic [21].

In this review, many different types of NP functionaliza-tion will be discussed using specific examples. A general approach by thiol/aminothiol, biomolecules, asymmetric group, post-polymerization, miscellaneous and their applica-tions will be outlined without attempting to comprehensively cover all the work that has been done in this field. We will first discuss the general aspects of functionalizing nanoparti-cles and will then highlight selected examples where this

4560 Current Medicinal Chemistry, 2010 Vol. 17, No. 36 Subbiah et al.

type of functionalization was used. Although many reviews on NPs and surface modification and functionalization of NPs for biomedical and nanotechnological applications al-ready exist, the present article aims at reviewing the different classes of functionalization and their synthesis methods, which are distinguished by the functional groups and specific application. In addition, we will discuss the use of function-alized NPs as a multifunctional tool in nanobiotechnology [22-24]. The increasing need for more efficient and less in-vasive methods to treat diseases is stimulating the develop-ment of new technologies in the field of nanotechnology including NPs functionalized with drugs, biomolecules and other chemical moieties used for therapy and diagnosis. Functionalized nanoparticles (FNPs) offer improved trans-port properties and pharmacokinetic profiles in vivo after systemic administration; they can penetrate deeper into tis-sues through fine capillaries and epithelial lining resulting in more efficient delivery of therapeutic agents to target sites [25]. Moreover, their dimensions impart remarkable phys-icochemical properties to the NPs system that are able to optimize some of the most important properties including solubility, diffusivity, distribution, release characteristics and immunogenicity and most importantly the ability to target the identified tissue with minimal distribution to normal tis-sues [26, 27]. Thus, FNPs hold promise for overcoming the failures of traditional therapeutics. According to a recent survey (Table 2), approximately 26 NPs based medicines have already been accepted for clinical use and numerous NPs are under clinical testing [28]. The basic components and their role in biomedical applications is schematically illustrated in Fig. (1).

A wide diversity of different methods has been devel-oped for NP functionalization with their specific applications

being the most widely investigated. NPs have been exten-sively investigated due to their advantageous properties such as their biodegradability and biocompatibility in physiologi-cal systems, natural abundance and suitability for chemical modification and functionalization of the NPs derived from various materials. This review provides an update on NPs functionalization and their specific applications in biomedi-cal science (therapy, diagnosis and sensors). An overview of the design criteria for functionalization will be briefly dis-cussed, followed by different functionalization groups that have been specifically used for medicinal applications. The most appealing aspect of the FNPs systems, namely targeted delivery, will also be summarized. Finally, future challenges, perspectives and directions will be discussed.

2. FUNCTIONALIZATION OF NANOPARTICLES

After NPs have been functionalized with chemical and biomolecules through a covalent bond, the bioactivity of the synthesized material should be carefully examined for any undesirable changes in intrinsic activity. The physicochemi-cal properties of the NPs, the size, distribution, surface charge and nature of the FNPs are likely to determine the in vivo fate of the delivery of the drug (Fig. 6). It is generally recognized that 20-200nm particles are suitable for systemic delivery of therapeutics. Particles larger than this size range are quickly up taken by the RES and rapidly cleared from the circulation, whereas particles within this size range can cross the fenestration in the hepatic sinusoidal endothelium, lead-ing to hepatic accumulation instead of long circulation times [29]. The targeting ability of NPs for site-specific delivery of drugs is paramount when the drug is delivered systemically. Targeted delivery concentrates the drug at the site of action

Fig. (1). General schematic of FNPs, their components, and multifunctional applications in the field of biomedicine.

Nanoparticles Current Medicinal Chemistry, 2010 Vol. 17, No. 36 4561

Table 1. List of Abbreviations

APS Aminopropyl silane

BBB Blood brain barrier

BSAP Bovine serum albumin particles

CT Computed tomography

DACH Diaminocyclohexane

DEAP-Lys N-(3-diethylamino) propyl isothiocyanato-L-lysine

DTIC 5-(3, 3-dimethy-1-triazenyl) imidazole-4-carboxamide

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EPR Enhanced permeability & retention effect

FLK Vascular endothelial growth factor receptor 2

FNPs Functionalized nanoparticles

HPMA N-(2-hydroxypropyl) methacrylamide

LHRH Luteinizing hormone releasing hormone

MPI Magnetic particle imaging

MPS (3-methacryloxypropyl) trimethoxysilane

MRI Magnetic resonance imaging

NPs Nanoparticles

N-C-F Nanoparticle-chelating agent-functional group

PASP Poly (aspartic acid)

PBCA Poly (butylcyanoacrylate)

PCL Poly ( -caprolactone)

PDLLA Poly (D,L-lactide)

PE Poly (ethylenimine)

PEG Poly (ethylene glycol)

PET Positron-emission tomography

PGA Poly (glutamic acid)

PHEO Poly (hydroxy ethyl oxide)

PHEP-Pal 2-(N-phthalimido) ethyl palmitate

PLA Poly (lactic acid)

PLGA Poly (lactic-co-glycolic acid)

PLLA Poly (L-lactide)

PNIPA Poly (N-isopropylacrylamide)

PPS Poly (propylene sulfide)

PSMA Prostate specific membrane antigen

PVA Poly (vinyl alcohol)

RES Reticuloendothelial system

RGD Arginine-glycine-aspartic acid

scTNF Single chain tissue necrosis factor

SMCC Succininamidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate

TDDS Targeted drug delivery system

THF Tetrahydrofuran

TOPO Tri-N-octylphosphine oxide


and potentially reduces any undesired effects at normal tis-sues. Also, it is essential to design NPs with a controllable release profile that satisfies the desired application. Better protection against environmental factors and more tunable control is achieved if loading is performed by encapsulation rather than adsorption on to the NPs. Successful combina-tions of these factors in the design of NPs are likely to lead to enhanced therapeutic outcomes, while reducing undesired effects at normal tissues.

Functionalization of the NPs can be defined as the addi-tion of a chemical functional group on their surface in order to achieve surface modification that enables their self orga-nization and renders them compatible. NPs have mainly been functionalized with thiols, disulfides, amines, nitriles, car-boxylic acids, phosphines and biomolecules [30-35]. The main goal of functionalizing NPs is to cover their surface with a molecule that possesses the appropriate chemical functionality for the desired application. In all cases, func-tionalization of the particles produces a drastic change in their surface properties. The surface chemistry of NPs is al-ready an important aspect of their synthesis, since this prop-erty can be exploited to control their size and self organiza-tion during formation. This can be achieved by complexing groups that bind on the surfaces during their formation and complex formation should not promote agglomeration. A significant amount of research has examined methods of modifying NPs and it would not be feasible to exhaustively cover this body of literature in a single review; therefore, this review will only discuss some representative examples of NPs functionalization, highlighting the work discussed above. In addition, we will focus on describing the richness of such chemistry and potential biomedical applications (Fig. (1)).

2.1. Methods of Functionalization

There are two strategies for introducing functional groups to surfaces and NPs. The first method is direct functionaliza-tion, where the whole functional ligand is a bi-functional organic compound. In this approach, one of the functionally reactive groups is used to attach to the NPs surface (com-plexing agent) and the second group contains the required active functionality (NPs surface modifying group). Direct functionalization is preferred because it only requires a sin-gle conjugation step. One limitation of the direct functionali-zation method is the incompatibility of the functional group F with the preparation process, for instance the modifying group may react with the particle surface [10]. Another rea-son to utilize a step-wise procedure is steric hindrance. An example of the interference of functional groups with the particle surface is the back bonding of amino or ammonium groups to the charged surfaces. In the case of silica particles covered with 3-aminopropyl groups (from the reaction with 3-aminopropyl-triethoxysilane), the zeta potential and thus particle agglomeration was controlled by the co-reaction with 3-(trihydroxysilyl) - propylmethylphosphonate. Back bonding of the NH2 groups to the particle surface was there-fore suppressed by the interaction between the amino and phosphonate groups [36]. For direct functionalization thiol, phosphine oxide, phosphonates, carboxylates groups have commonly been used in the case of chalcogenides, oxide

NPs, and noble metal NPs. The binding strength of the com-plexing molecule must be high enough to ensure maximum surface coverage. This is of particular importance, especially when the complex-functional molecule is grafted in substitu-tion of the complexing agent that was previously used for the synthesis of the particles. In this sense, it would be best to utilize polydentate ligands, such as dithiols or oligomeric phosphines which bind much more strongly to the surface [37]. Functionalization methods are graphically described in Fig. (2).

The second method is post-functionalization, which is generally preferred because this strategy is more versatile and the nature of the functionalizing moieties may not be fully compatible with good control over the size and disper-sion state of the particles in the solvent used for their synthe-sis. This describes a bifunctional compound where a binding-chelating group is reacted first and the group of coupling site can be converted, in a second step, to the final functional group F. Post-functionalization of the particles requires a molecule to be grafted on the surface such that it has a struc-ture that can be described as N-C-F (Nanoparticle-Chelating agent-Functional group). For post-functionalization, silane-like compounds have been generally used. Hydroly-sis/condensation reactions lead to the formation of a silane like coating around the particles with a fraction of the func-tional group orientated towards the outside of the particle. This process has been used in many systems, mostly in oxide systems [38], but it has also been investigated in the case of chalcogenides [39]. The main advantages of this approach come from the large number of commercially available si-lane coupling agents, the chemistry of which is well docu-mented. In addition, the core/shell structure ensures a strong binding of the functional groups with a high surface cover-age. The main problem with this method is that the func-tional group must have a high affinity to the surfaces of the particles and cannot exist as isolated clusters. Unavoidable clusters must be eliminated with special care.

Other functionalization processes have also been used, including the encapsulation with a polymer that possesses both the chelating and the functional group. This novel ap-proach has been used for TOPO capped CdSe/ZnS particles, which consists of retaining the TOPO molecules, and graft-ing a functionalization molecule in which the complexing group is a long alkyl chain that interacts with the octyl groups through hydrophobic interactions [40, 41].

2.2. Class of Functionalization

Thiol/Aminothiol

The thiol conjugation method, which was initially pro-posed by Brust et al, has been widely used for NPs function-alization [42]. Guerrero et al synthesized three kinds of thiol FNPs. Initially they synthesized thiol functionalized gold (Au) clusters through Au-S bonds with dodecanethiol and octanethiol molecules, named Au-SC12 and Au-SC8 [43], based on the method of Brust et al. In addition, Au NPs capped with both octanethiol and thiolated undecanoic acid molecules, named Au-SC8/SC11COOH, were also fabricated based on the method of Simard et al synthesis [44]. Finally water soluble Au NPs capped with tiopronin (Au-ST) were synthesized based on the method of Templeton et al [45],


which utilizes a synthetic thiol containing biomolecule. Thiol chemistry is one of the most developed functionalization methods used for the fabrication of functional NPs. Fig. (3) describes the chemical functionalization reaction of thiols. Sulfur compounds naturally form strong coordination bonds with many metals including Ag, Cu, Pt, Hg, Fe, Si, and Au [46]. Sulfur and organosulfur have a high affinity for metal surfaces and thus will adsorb spontaneously [47]. Thiol or disulfide capped NPs can be prepared by either the direct functionalization method where the metal precursor and the protective ligand are reacted simultaneously.

Another method based on thiol chemistry is the post-functionalization method, where the sulfur compounds are grafted on the surface of presynthesized NPs that are covered by solvent molecules and are thus replaced by sulfur contain-ing ligands [10, 30, 31, 36, 48-50]. Li et al reported on the immobilization of trypsin using amine functionalized mag-netic NPs [51]. Brousseau et al prepared dimers of Au NPs by ligand exchange reactions of citrate capped Au NPs with dithiols [52]. Shen et al covalently conjugated triphenyl phosphine to thiol group functionalized 5nm Au NPs and demonstrated their potential application in the electrochemi-cal detection of the anticancer drug Dacarbazine [5-(3, 3-dimethy-1-triazenyl) imidazole-4-carboxamide; DTIC]. Likewise, FNPs were used to facilitate the specific interac-tions between anticancer drugs and DNA or DNA bases [53].

Bio-Functionalization

NPs functionalized with biomolecules have recently at-tracted great interest because the resulting hybrid materials have proven to be useful as drug carriers. Small biological molecules such as amino acids can be anchored to the sur-

face of the NPs, opening the possibility of attaching func-tional biomolecules to bio FNPs. Sousa et al studied the pos-sibility of employing both aspartic and glutamic acids as chelating agents for the synthesis of NPs [54]. Tie et al re-ported a two step synthesis of NPs by directly anchoring different amino acids such as leucine, arginine, cysteine and tyrosine to the NPs surface [55]. Viota et al successfully attached different amino acids to FNPs with the aim of pro-ducing biological functional NPs [56]. Wampler et al pro-duced Au NPs functionalized with proteins and investigated the mechanical properties of the resulting NPs, which could be used to tune the properties of biomolecular films [57]. Koh et al modified -Fe2O3 NPs with aminopropyltriethoxy silane and concluded that the functionalized antibody IgG retained a 50% binding activity [58]. More recently, the use of N-(2-aminoethyl)-APS (AEAPS) for the surface modifica-tion of iron oxide NPs have become a popular method for the covalent attachment of antibodies such as anti-CD34, as re-ported by Chen et al [59]. In addition, NPs modified with molecules such as organosilane, vinyl alcohol/ vinyl amine co-polymer were used for subsequent conjugation of anti-bodies, which could then be utilized for targeting specific biological cells and tissues [60]. Li et al used lipid NPs func-tionalized with an integrin antagonist (anti-FLK-1 antibody) to target the monoclonal antibody for antiangiogenesis ther-apy wherein the NPs were labeled with

90Y for radioimmu-

notherapy [61]. Dharap et al developed a molecular targeting camptothecin (anticancer) drug delivery system using BH3 and LHRH peptides functionalized polymeric NPs to treat ovarian cancer [62]. Missailidis et al developed a targeted delivery system through the successful functionalization of aptamer molecules to polymeric NPs to increase the specific-ity against a C595 monoclonal antibody [63]. In addition,

Fig. (2). Schematic representation of functionalization methods. Direct functionalization, which uses a conjugating agent in order to directly

attach the chemical moiety, and post-functionalization, which uses a binding/chelating agent to attach to the NPs and a secondary functional

group for covalent attachment of the biomolecule of interest.


HPMA NPs were functionalized with Arginine-Glycine-Aspartic acid (RGD) peptides along with radionucleotides and drugs to target cell adhesion molecules such as integrins for applications in cancer treatment [64].

Asymmetric Group

Colloidal NPs with controlled size, shape and composi-tion can be synthesized using state of the art nanomaterials [65, 66]. Nevertheless only highly symmetric NPs such as spheres, rods, and more recently tetrapods have been exten-sively analyzed [67-70]. Nanomaterials of greater complex-ity can be built with lower symmetry components, offering the possibility of creating materials with a higher level of integrated functionality. Asymmetric nanostructures are more versatile building blocks compared to their symmetric counterparts [71]. For example, Au NPs were asymmetri-cally modified with single strand DNA, which can be used as the building block to prepare more complex structures such as dimers and trimers [72, 73]. Recent studies have been demonstrated that asymmetric diblock Au-polymer nanorods can self-assemble into bundles, tubes, and sheets [74]. Love et al synthesized Au half-shell structures by evaporating Au on to an array of silica colloidal particles, which is simply known as the post-functionalization method [75]. Lu et al reported that further heat treatment of these structures pro-duced Au-metal oxide asymmetric dimers [76]. Similarly, Au shell structures were grown on a silica surface to produce Au cups or caps [77]. The asymmetric structure in the nano rod system has also been realized using the chemical vapor deposition technique, which is known as the direct function-alization method [78-80]. Likewise, asymmetric rods can be synthesized using template directed growth [74, 81]. How-ever, when this approach is used, relatively large particles are produced. For example, the Au-metal oxide asymmetric dimers can only be prepared from metal oxide particles larger than 200nm. The Au-polymer asymmetric nanorods have diameters around 200nm and lengths over 1 m. As a result, they can only be used to prepare particles with dimen-sions of m or larger. To synthesize nanometer sized assem-blies, smaller asymmetric building blocks are needed. Fur-thermore, it is desirable to develop a range of methods that can yield such structures. The structure of the tetrapod is topologically similar to that of a sp

3 hybridized carbon atom.

This kind of structure can serve as a building block to pre-

pare superstructures, especially 3D superstructures, by mim-icking the bonding between carbon atoms and organic mole-cules. Liu et al successfully prepared asymmetrically func-tionalized Cd/Te tetrapods and nanorods via a site selective modification method [71]. The properties of the synthesized products were previously compared with the asymmetric product produced by Banin and co-workers [82]. Hence tetrapods or other such materials can be used as building blocks for asymmetric functionalization. Rajesh et al de-scribed a simple asymmetric functionalization technique to produce Au NPs with reactive ligands localized to a small region of the Au NPs surface and assembled the particles together to form dimers [83]. The advantage of this approach is that the ligands in a spatially limited region of the surface may be used for further chemistry and the rest of the ligands can be selected to remain unreactive during any coupling process [84].

Polymers in Functionalization

Research on the synthesis of colloidal NPs by the top-down or bottom-up methods has recently dramatically in-creased. The polymer matrix embedded in the NPs plays a major role in dictating the compatibility of the NPs for appli-cations in harsh environments such as in acidic and alkalic solutions [85]. Also polymer NPs are widely used in phar-maceuticals application particularly cancer therapy and drug targeting (see Tables 2, 3, 4). In polymeric nanocomposites synthesis, NPs or nanofibers have been used as fillers to im-prove the properties of the nanocomposites [86-88] such as strength, which is very important in tissue engineering appli-cations. The filler and the polymer linkage is poor when the nanocomposites are prepared by simple mixing, which pro-duces artificial defects and consequently decreases the me-chanical property of the nanocomposites [89-91]. To over-come this problem, an appropriately engineered interphase will be required, which will also improve the strength, toughness and compatibility of the composites [92]. The interfacial interaction of the NPs and the polymer matrix is an important factor in improving the quality and properties of the nanocomposites [89, 90]. Nevertheless, functionaliza-tion of NPs with polymers requires a surfactant to produce a strong bond, stabilize the NPs and render the NPs compatible with the polymer [93]. Zhanhu Guo et al synthesized poly-mer functionalized alumina NPs using neutral MPS (3-

Fig. (3). Schematic of the thiol group based functionalization.


methacryloxypropyl) trimethoxysilane) in a tetrahydrofuran (THF) solution where alumina NPs and MPS were used as a filler and surfactant, respectively [85, 91, 94, 96]. Abboud et al developed a method using a high temperature reaction at the silane toluene refluxing point to functionalize NPs with MPS [97]. Ultimately the polymer functionalization en-hanced the mechanical properties of the NPs and no deleteri-ous effects were reported. In addition, this nanocomposite did not dissolve in acidic and basic medium [85]. Rothenfluh et al synthesized polymer FNPs using the phage display technique and were able to use these FNPs to carry a hydro-phobic drug [118]. In addition, the bioavailability can be improved by post-polymerization. 38nm PPS NPs were syn-thesized and immobilized with a ligand specific for articular cartilage, which was then covalently grafted to the emulsi-fier. In addition, post-polymerization using a copolymer such as pluronic led to a 72 fold increase in targeting to the ex-tracellular compartment of articular cartilage [98-102]. Post-polymerization of the NPs with polymers like PEG produces the stealth effect, which is an established method to achieve long-term in vivo circulation and reduce clearance by RES [103, 104]. The polymerization approach is schematically illustrated in Fig. (5).

Miscellaneous

Viral NPs with modified chemical groups have been ob-tained from acidic hot spring in Iceland and can be used in a variety of harsh conditions such as the acidic environments found in the body [105]. In addition to the functionalization methods described above some other methods have also been examined. Dendritic NPs structures were the first nanomate-rials that could be used for precise stoichiometrical function-alization since the stoichiometries were mathematically de-fined by geometric restrictions [106]. Hainfeld et al reported the stoichiometrical monofunctionalization of Au NPs [107]. Worden et al reported stoichiometrical functionalization of Au NPs via solid-phase chemistry and polymerization method [108, 109].

3. IMPLICATIONS OF FNPS IN BIOMEDICAL

SCIENCES

Nanomedicine and clinical treatments hold promise to benefit from the considerable investments being made in nanotechnology research [110]. Nanomedicine depends on several overlapping molecular technologies and advances in

Fig. (4). Covalent attachment of biomolecules such as antibody and antibody fragments using coupling agent EDAC and SMCC respectively.

The label NH2 (A) designates the covalent cross linking reaction and SH (B) designates sulphhydryl-amine coupling reaction respectively.

Fig. (5). Schematic showing the procedure used for FNPs preparation by the post-polymerization method using a surfactant.


other fields including 1) Construction of nanoscale sized structures for diagnostics, biosensors, and drug delivery, 2) Ongoing advances in genomics, proteomics and nano-engineered microbes, 3) The creation of molecular machines to identify and eliminate host pathogens, in tissue engineer-ing and replacing/repairing cells or cellular components in vivo [111]. Research into the delivery and targeting of thera-peutic and diagnostic agents with NPs is at the forefront of nanomedicine due to the inefficient formulations of oral and injectable drugs for certain products, which have novel de-livery requirements such as optimizing efficacy, minimizing side effects and improving patient compliance. NPs size in the formulation can enhance bioavailability, sustained re-lease of drugs and enable more precise targeting to the level of direct intracellular delivery. Moreover, small size NPs can bypass the blood brain barrier, pulmonary system and the tight epithelial junctions of the skin, all of which are vital to targeted drug delivery [112].

3.1. General Consideration of Nanoparticles Application

In pharmaceutical applications such as drug delivery, the most important aspect of the NPs or nanocarrier is its stabil-

ity during the course of blood circulation. Drugs must be stably loaded into the NPs without leakage or catabolism by enzymes in the blood. NPs must avoid glomerular excretion by the kidney and uptake by the RES in the liver, spleen and lung. Since there is a molecular weight threshold for glome-rular filtration (42,000-50,000 for water-soluble synthetic polymers), elimination by this mechanism can be avoided by increasing the molecular weight of the NPs. Carriers in the blood circulation may also induce nonspecific complement activation and opsonization, resulting in the drug’s elimina-tion from the blood compartment due to RES recognition. In this regard, it is crucial to modify the NPs surface with bio-compatible materials such as PEG to provide a ‘stealth’ characteristic. The second challenge for drug delivery appli-cations is that the NPs carriers must permeate tumor blood vessel to access the target tissue. One of the most important advantages of macromolecular carriers is their preferential accumulation in solid tumors. Such an elevated tumor accu-mulation is facilitated by microvascular hyper permeability and impaired lymphatic drainage in tumor tissues known as the enhanced permeability and retention effect (EPR) (Fig. (6)). In this case the carriers should be small enough (<100nm) to allow effective transport from the blood com-

Fig. (6). Programming FNPs for specific tissue delivery using a targeting ligand. Model of cancer cell specific targeting through both passive

(EPR effect) and active tissue targeting, which is shown in the dotted inset image. Cationic charged FNPs are more likely to have an in-

creased affinity to the cell membrane compared to anionic FNPs. Factors affecting FNPs based drug delivery and possible toxicity of FNPs is

also shown along with the example of ROS (Reactive oxygen species) mechanism of cell death.


partment into solid tumors. The third challenge is selective uptake into the target cells. In this regard, an attractive strat-egy is ‘active targeting’, which exploits cell surface receptors by installing moieties onto the carriers that specifically rec-ognize the target cells. Finally, controlled intracellular traf-ficking or organelle targeting is important to enhance me-dicinal effects, such as nuclear targeting in the case of gene delivery. Carriers ranging from 5 to 100 nm in size are inter-nalized into cells by the endocytotic pathway, where en-dosomes and encapsulated carriers are separated from the cell membrane by a process of inward folding. These en-dosomes have an acidic pH value (5.5) and eventually fuse with lysosomes, where drugs can be degraded by a host of lysosomal enzymes [131]. Therefore, careful modulation of both size and surface properties is required for functionality and pinpoint targeting, which allow for the maximum me-dicinal effect to be realized. The role of FNPs in medicine such as drug delivery by passive and active tissue targeting, and factors affecting the FNPs therapy and their toxicity is graphically illustrated in Fig. (6). The application of FNPs in pharmaceutical sciences will be described henceforth by considering the above issues. Many NPs based therapeutic drugs are available in the market as listed in Table 2.

3.2. Therapy

Polymeric NPs have been designed to augment drug con-centrations in blood or vascularized tissues and aim to reduce a drug’s toxicity and to improve its therapeutic effects [114-117]. Rothenfluh et al reported on the development of a novel NPs based drug delivery system for intra tissue drug release in articular cartilage, which may prove useful in drug and biomolecular therapy in diseases such as osteoarthritis [118, 119]. The interaction of surface charged FNPs with the endosomal membranes of the cells is schematically shown in Fig. (6). Different types of NP functionalities have been ex-

plored with the goal of allowing the NPs to enter (endocyto-sis) or disrupt the membranes of pathogenic micro organisms and tumor cells. Polymer-based NPs alone do not have ca-pacity for cell-specific targeting but provide flexible chemis-try for the attachment of cell specific targeting agents that allow for both increased cell uptake and often cell specific-ity. Many membrane-bound receptors can be used for target-ing via receptor mediated endocytosis. NPs with glycosidic moieties [120-122] and other small molecules such as folate provide selective targeting to cell types that displays the appropriate receptor protein [123]. Asialoorosomucoid functionalized with poly-lysine to target the asialoglycoprotein receptor on hepatocytes and NPs functionalized with iron- transport protein transferrin [124-128] are the two classic examples of cell targeting using functionalized NPs. The success of the targeting strategy is dependent on the conjuga-tion chemistry used for functionalization, the length of the spacer between the ligand and NPs, the ligand receptor bind-ing strength and the number of targeting ligands per NPs. Efficient cell-specific targeting always requires careful opti-mization of the various parameters that affect cell-surface binding because of nonspecific electrostatic binding to the surface of non-targeted cells [129].

3.3. Cancer Therapy

Cancer remains one of the world’s most devastating dis-eases. Although there are more than 10 million new cases every year [130], the number of deaths due to cancer has been reduced in the past few years due to the development of new technological systems, which have been developed based on a better understanding of tumor biology, improved diagnostics systems and treatment modalities including sur-gical intervention, radiation and chemotherapy. Chemothera-peutics often also kill healthy cells and cause toxicity to pa-tients [131]. Developing chemotherapeutics with increased

Table 2. Representative examples of nanoparticles based therapeutics for Cancer [113, 28]

Company Drug Company Drug

Abraxis Albumin bound paclitaxel American pharm partners Albumin bound paclitaxel

Gilead Sciences Liposomal daunorubicin Keroes Ligand targeted emulsion containing NPs for cancer

Ortho Biotech Liposome-PEG doxorubicin Nanobiotix Nanobiodrugs for cancer treatment

Skyepharma Liposomal cytarabine Introgen therapeutics NPs to target cancer

Zeneus Liposomal doxorubicin Liplasome pharma Lipid based nanocarrier for targeted delivery

Enzon PEG-GCSF Samyang Liposome-PEG doxorubicin

Bio Alliance Pharma

Polyglutamate paclitaxel Amgen Methoxy-PEG-Poly(D,L-lactide) taxol

Transcave Liposomal annamycin Phoenix HPMA copolymer-DACH platinate

GP-Pharm Liposomal cisplatin Acusphere Nanocrystalline paliperidone palmitate

Inex, Exon Liposomal fentanyl Schering-plough Liposome-PEG doxorubicin

OSI Pharm., Liposomal doxorubicin Cell therapeutics Polycyclodextrin camptothecin

Supratek Pharma PEG-camptothecin Insert therapeutics Pluronic block-copolymer doxorubicin

Callisto PEG-L-asparginase Cell therapeutics Polyglutamate camptothecin

Access Pharm., Liposomal vincristine Elan entermed Poly(iso-hexyl-cyanoacrylate)doxorubicin


activities and less toxicity can be achieved by either pas-sively or actively targeting cancer cells. A nano based target-ing system reached clinical trials in the mid 1980s then dur-ing the 1990s the first product based on polymeric liposome and polymer protein conjugates were marketed. More recent studies have focused on creating therapeutics based on the targeting strategy of NPs and nanocarrier systems that have been approved for wider use. This can be achieved by conju-gating nanocarriers with drugs and ligands that bind to over expressed antigens or receptors on the target cells. Fig. (6) illustrates the targeting of tumor cells with functionalized nanosystem containing therapeutics and the numerous barri-ers that this technology encounters based on the principle of EPR [131]. Many research groups have experimented using liposomes, NPs and other nanomaterials and have suggested that the most effective threshold size is <200 nm for better extravasations into tumors [132-135]. Targeting approaches suffer from several limitations such as the inefficient diffu-sion of nanosystems to the tumor cells, which might induce multiple drug resistance and render many potential drugs inactive. One way to overcome this limitation is functionali-zation, so that it can actively bind to the specific cells after extravasations. Ligand functionalization can be used to achieve active tissue targeting through a variety of conjuga-tion chemistries [134]. It is imperative that the agents bind with high selectivity to molecules that are uniquely ex-pressed on the cell surface. To maximize specificity, a sur-face marker should be over expressed on the target cells where the ligand FNPs may cause receptor mediated inter-nalization to release the drug inside the cells [136]. It is gen-erally known that higher binding affinities increase the tar-geting efficacy. In addition, multivalent avidity may be used to improve targeting. Agents such as proteins mainly anti-bodies and their fragments, nucleic acid, or other receptor ligands such as peptides, vitamins and carbohydrates can be used for targeting. Furthermore, it is possible to increase the binding affinity and selectivity to cell surface targets by en-gineering proteins that detect a specific conformation of a drug target receptor. Peer et al used a fusion protein consist-ing of a scFv antibody fragment to target and deliver small interfering RNA to lymphocytes where a 10000 fold in-creased affinity for the target receptor, integrin LFA-1 was observed [137]. The types of NPs and FNPs, their size and type of drug that have been used for cancer therapy are listed in Table 3.

3.4. Drug Delivery

One of the basic goals of pharmacology is delivery of the right drug, right dose at the right time to the right patient so as to optimize the therapeutic efficacy of the drug. In this regard, drug delivery is one of the most important factors in the field of pharmacology. Nanotechnology may prove vital to fulfilling the goals of drug delivery. The more traditional ways of viewing drug delivery is to look at different routes of drug administration, such as oral, parenteral, transdermal and inhalational. Throughout the history of medicine, there has been a need to develop alternative methods of delivering a drug to a patient. The primary goals of novel drug delivery approaches would be to provide an easy route of administra-tion, ensure patient compliance, decrease toxicity, improve bioavailability and achieve precise therapeutic targeting.

Technologies associated with drug delivery are now com-monly used to create and extend the potency of the drug. The discovery of better delivery systems, in conjunction with the discovery of new pharmacological compounds, will poten-tially advance disease diagnosis and treatment beyond our wildest expectation [22]. Nanotechnology now is a crucial factor in the development of novel drug delivery systems and it has significantly impacted the field of drug delivery in the last decade. Nanotechnology is being used to manipulate not only the size of the drug particles but the physical character-istics and thus the extent and location of drug delivery. NPs have tremendous applications in therapeutics [28] and trans-dermal vaccine delivery [180]. Nanotechnologies will again be examined as they relate specifically to drug delivery. The application of nanotechnology to the diagnosis and treatment of cancers is seen as nanotechnology’s largest public health contribution. Nanotechnology shifts the techniques from microfabrication, such as osmotic pumps, to secondary nanometer sized constructs (microspheres). Orringer et al describe targeting brain tumors with NPs through antigen dependent specific or nonspecific mechanisms [181]. Formu-lation science has formed a unique bridge with computer technology for the creation of a controlled-release microchip capable of infinite modulation [182]. The targeted delivery can be fulfilled by stimuli induced targeting based on physi-cal properties, such as the magnetic induction between mag-netic NPs and a magnet at the site of action and cell or tissue specific targeting based on a strong affinity between a ligand and target receptor, such as the RGD peptide to a specific cellular receptor or mineral affinity of biphosphonates (BPs) to the mineral phase of bone [183].

3.5. Targeted Drug Delivery System (TDDS)

One of the most promising attributes of NPs is their po-tential for targeting to specific tissues and their ability to carry multiple drugs and/or imaging agents. It is possible to increase the local drug concentration by carrying the drug within the NPs and releasing it when it is bound to the tar-gets. TDDS would be targetable to individual cellular ad-dresses within specific tissues and organs. Currently, natural, synthetic polymers and lipids are typically used as drug de-livery vectors. While offering great opportunities, designing tissue seeking NPs is a challenging task that requires over-coming physiological and biochemical barriers [184]. For intravenously administered NPs, the in vivo fate of NPs is predominantly determined by their size and surface charge. NPs size restricted to <200nm and functionalized with poly-mer to avoid opsonization and subsequent phagocytosis and to remain in circulation for sufficient time to reach the tar-geted site. For instance, the BBB restricts the transportation of even small molecular weight drugs, hydrophilic com-pounds and charged molecules from circulation to the central nervous system, likewise bone possesses a membrane that consists of lining cells, which function as a marrow blood barrier with pores of approximately 80-100nm [185]. Thus, identifying targeting ligands and designing the appropriate NPs are keys for successful delivery of drugs to the site of action at therapeutic levels for a desired period of time (Fig. (6)). Polysorbate FNPs are known to result in greater trans-port of NPs across the BBB [186]. NPs are capable of spe-cifically and locally delivering drugs and other therapeutics


Table 3. NPs and FNPs that have been Used for Cancer Therapy

Nanoparticles Size (nm) Drug Indications Refs.

PCL 250-300 Tamoxifen Breast cancer [138]

Human serum albumin (amino or COOH group) 150-500 Doxorubicin Antineoplastic [139]

PBCA 178 Doxorubicin Dalton’s lymphoma [140]

Trimyristin (sterically stabilized) 200 Paclitaxel Ovarian, lung breast cancer

[141]

PVA polymeric micelles - Polymer P10(4) Neuroblastoma, melanoma [142]

PEG-PASP 50 Doxorubicin Leukemia [143]

PLLA-b-PEG (folate targeted) 50-80 Doxorubicin Solid tumors [144]

PNIPA-b-PDLLA 60 Paclitaxel Ovarian, lung breast cancer

[145]

PEG-PE/egg phosphatidylcholine (lipid conjugated) 100

100

Paclitaxel

Paclitaxel

Various cancer

Various cancer

[146]

[147]

Nucleosome-specific monoclonal Ab functionalized 11 Camptothecin Various cancer [148]

PEG-lipid 10-40 Tamoxifen Lung carcinoma [149]

Polymer-lipid hybrid NPs 290 Doxorubicin Solid cancer [150]

Poly(2-ethyl-2-oxazoline)-b-PCL 30-80 paclitaxel Various cancer [151]

Poly (benzyl-L-aspartate)-b-PHEO 37 Doxorubicin Antineoplastic [152]

PCL-b-trimethylene carbonate-PEG (serum protein) 96 Ellipticin Anticancer [153]

PGA-b-PEG 40 Doxorubicin Solid cancer [154]

PDLLA-b-methoxy PEG 30 Paclitaxel Various cancer [155]

Pluronics 10-100

10-100

Doxorubicin

Carboplatin

Colon cancer

Colorectal cancer

[156]

[157]

PCL-b-methoxy-PEG 78

<200

Cisplatin

Paclitaxel

Anticancer

Ovarian &breast cancer

[158]

[159]

PLGA-b-PEG - Docetaxel Prostate cancer [176]

Au NPs <50 Gemcitabine Lung, breast, pancreatic & bladder cancer

[2]

Silica based NPs 30 Photodynamic therapy Various cancer [160]

Au -conjugated cytomegalovirus NPs <2 phototherapy Solid tumors [161]

Anti-HER2 antibody-targeted Au /silicon NPs 60 Nanoshell assisted photo thermal therapy

Metastatic breast cancer [162]

Aminosilane-coated iron oxide NPs 3-15 Thermotherapy Brain tumors [163]

Starch-coated iron oxide NPs 20-30 Magnetically guided mitoxantrone

Tumor angiogenesis [164]

6-PAMAM <10 Avidin-G6Gd Intraperitoneal disseminated tumor

[165]

5- PAMAM 40-100 Methotrexate Chemotherapeutics [166]

Folic acid-PAMAM dendrimers Methotrexate Epithelial cancer [167]

Poly (glycerol-succinic acid ) dendrimers <10 Camptothecin Colon, ovarian, lung cancer.

[168]

PEG-PLGA 105 Doxorubicin Various cancer [169]

PEG-PCL 50-130 Paclitaxel Various cancer [170]

cGRD peptide in PEG-PCL 20-40 Doxorubicin Various cancer [171]

Galactose in Poly (L-benzyl L-glutamate)-PEG 104 Paclitaxel Various cancer [172]

Glycol chitosan NPs - Doxorubicin Solid tumors [173]

Albumin bound-PEG NPs - Doxorubicin, Various cancers [174]

mAb 2C5 mAb 2G4 20 Paclitaxel Various cancers [175]

Antibody-enzyme-conjucated NPs - Ab-directed enzyme prodrug

Ovarian cancer [176]

Biotinylated antibody-conjugated micelles - Daunomycin Brain tumor [177]

Anti-PSMA aptamer 168 Docetaxel Breast, lung cancer [178]

PHEP-Pal 40-100 Phthalidimide Anticancer [179]

- not available.


agents through a novel process known as contact facilitated drug delivery [187]. The direct transfer of lipids and drug from the NPs layer to the targeted cell is usually a slow and inefficient process; however, this can be accelerated by minimizing the separation between the lipids and NPs sur-face and increasing the frequency and duration of the lipid-surface interactions. Interestingly, TDDS in the form of pharmacytes has been recently reported. In this regard, the NPs were relatively passive and acted as a nanorobot that was 1-2μm in size. Pharmacytes can carry up to 1μm

of a

pharmaceutical payload and can deliver this payload directly into the extra cellular fluids or into the cytosol. There are several potential uses of pharmacytes particularly for the targeted delivery of cytocidal agents to tumor cell. Another potential area of application is the control of cell signaling processes with a functionalized antibody and biochemical substances [188]. FNPs, targeting ligand, size of the FNPs,

tested drug, target organ and indication for TDDS are shown in Table 4.

3.6. Gene Delivery and Tissue Engineering

Tissue engineering applications have also trended towards the development and implementation of nanometer sized components. Tissue engineering typically involves the fabrication of biological constructs that will restore, maintain and improve tissue function [214]. One common strategy is to isolate cells of interest and grown them in culture to form a three-dimensional (3D) tissue, which can be genetically modified in vitro before transplantation The resulting cell tissues can be encapsulated with NPs and functionalized with growth factors, then transplanted into the body within polymeric 3D matrices, which creates the potential for targeted tissue development and provides mechanical support for the

Table 4. Functionalized Nanoparticles for Targeted Drug Delivery

Nanoparticles Agent Size (nm) Drug Target organ & Indication Refs.

PLGA Alendronate 40-60 Estrogen Bone-osteoporosis [189]

Poly(DEAP-Lys)-b-PEG -b-PLLA block copolymer

poly(lysine) 165 Doxorubicin pH sensitive tumor targeting [190]

Protein NPs Albumin bound 130 Paclitaxel Tumor cells- breast cancer [191]

Magnetic NPs Meso-2,3-dimercaptosuccinic acid

8.1 Drugs Lungs- various diseases [192]

Magnetic NPs Luteinizing hormone release hormone

15 Imaging Brest cancer cells- cancer diagnosis [193]

Superparamagnetic NPs PEG 40-50 Drug & genes Fibroblasts- cancer [194]

Au NPs 5-Thiol modified aptamer 32 Scattered light photo illumination

Brest cancer cells- cancer diagnosis [195]

PLGA-b-PEG-COOH PSMA 70-250 Anti cancer Prostate- cancer [196]

BSAP Folate 70 Various drug Folate receptor- cancer [197]

PEG or PE hydrogel particles Transferrin <100 Oligonucleotide Brain- gene therapy [198]

Magnetic NPs Insulin 20 Drugs & genes Insulin receptors- cell therapy [199]

PLLA-PEG NPs Biotin 100-150 Anti cancer Cancer cells- cancer therapy [200]

Polystyrol NPs Sc-TNF 190 Anti cancer Cancer cells- cancer therapy [201]

PLA Nucleic acid aptamer 250 Anti cancer Prostate epithelial cells- cancer [202]

Liposomes ECM proteins intgrins 100 Raf genes Melanoma cells- cancer [203]

PE RGD peptides 100 siRNA Tumor vasculature- cancer [204]

Albumin Fibrinogen - Radioisotopes Tumor vasculature- cancer [205]

PLGA MP lipid A 357 - Dentritic cells [206]

Liposomes Folate 110 Doxorubicin Leukemia cells- cancer [207]

Liposomes CD19 - Doxorubicin B-cell lymphoma [208]

Liposomes HER2 receptor 110 Doxorubicin HER2 cells [209]

mPEG/PLGA Peptidomimetics 50-300 Various Brain cells [210]

Liposomes Hyaluronic acid 120-170 Doxorubicin CD44+ melanoma cells [211]

PLA Galactose 50-280 Retinoic acid Hepatocytes [212]

Viral particles Von willebrand factor - Cyclin gene Pancreatic cells- cancer [213]

- not available.


developing tissues [215]. The major obstacles in tissue engineering included a limited half-life and stability of growth factors proteins in vivo and the degradation of protein and polymeric matrices during release from the polymer caused by moisture, temperature, pH, etc., Gene therapy approaches are now being investigated for tissue regeneration to address some of the limitations in the current tissue engineering strategies. Gene therapy can be defined as the treatment of human diseases by the transfer of genetic materials into specific cells of the patients [216]. The genes of interest can be cloned into an expression plasmid and used as a DNA complex for tissue regeneration using viral and non-viral gene delivery vectors. In the age of genetic manipulation and gene delivery, transfection systems on the nanoscale are being custom-tailored using a variety of materials for different ap-plications particularly for patients that suffer from lost, defi-cient or failing tissue and require tissue transplantation. This technology has been and will be developed from a multidis-ciplinary perspective (particle mediated gene therapy) and encompass concepts developed in the fields of gene therapy and tissue engineering. Delivering DNA with polymeric ma-trices such as collagen, PLGA and alginate hydrogels was previously reported [217]. The combination of these fields involves the functionalization or incorporation of genes/proteins onto NPs, which can then be implanted or injected to promote tissue regeneration and treat genetic dis-eases such as hemophilia, muscular dystrophy, and cystic fibrosis through replacement of errant genes within the af-fected cells. In this regard, gene therapies also being devel-oped for cardiovascular, neurological, infectious diseases, wound healing and cancers by delivering genes to augment naturally occurring proteins, to alter the expression of exist-ing genes, or to produce cytotoxic proteins or prodrug acti-vating enzymes to kill tumor cells [218]. The list of possible therapeutic genes and delivery is extremely broad and en-compasses a wide array of factors involved in the growth and differentiation of the various tissues in the body. Makhluf et al surface modified PVA-Fe3O4 NPs with (3-aminopropyl) trimethoxysilane through amidation and used this system as a protein carrier into sperm cells and demonstrated that the antigenicy of the resulting conjugates was maintained [219].

3.7. Diagnosis

Over the last decades, tomographic imaging methods such as Computed Tomography (CT), MRI and Positron-Emission Tomography (PET), have become indispensable tools for the diagnosis of a large number of diseases. While PET provides high sensitivity in static imaging based on tracer materials, MRI and CT offers intrinsic tissue contrast at high spatial resolution and dynamic imaging. Real time imaging of 3D volumes using MRI remains challenging, whereas the limitations of CT involve the use of ionizing radiation. Gleich and Weizenecker presented a new imaging modality called magnetic particle imaging (MPI), which po-tentially offers quantitative 3D real-time imaging using mag-netic NPs [220-223]. Therefore it could become the modality of choice for diagnoses requiring fast dynamic information. In this regard, hybrid organic-inorganic NPs are being used and are thought to hold promise for use as novel nanocarrier probes for biological applications such as MRI, MPI, PET, hyperthermia inducing agent, magnetically controlled media

for the sensitive detection of biomolecules and diseased cells, etc., Among all the different types of NPs, iron oxide NPs are recognized as the most promising tool for imaging and site specific delivery of drugs and other bioactive molecules. Functionalized magnetic NPs will improve tracer response and will make the MPI, a capable in vivo new imag-ing modality, and has the potential to become a clinically adopted imaging method. Magnetite NPs, which were first surface-modified with aminopropylsilane (APS) and conju-gated with methotrexate, have been shown to have combined advantages in their therapeutic functionality to treat tumors, such their ability to monitor, through magnetic resonance imaging, real-time drug delivery to the treated tumors, pro-duce a controlled drug release profile, and result in a high uptake of the conjugate in the tumor cells [224]. Xu et al reported on the preparation and inclusion of magnetic NPs into surface modified PEG coated silica NPs as a matrix for encapsulation of certain reagents, for application for in vivo diagnosis, analysis, and measurements inside intact biologi-cal systems [225]. Yan et al studied the synthesis and charac-terization of silica functionalized iron oxide NPs for MRI [226]. Koo et al recently reviewed the literature relating to brain cancer diagnosis and therapy with nanoplatforms of polymeric iron oxide NPs based drugs [227]. Based on this previous research, functionalized iron oxide NPs do not seem to affect enzyme activity.

4. THE FUTURE PERSPECTIVES

Functionalization of NPs provides a unique bridge from materials to medicine and back and is becoming indispensa-ble to the discovery and development of innovative therapeu-tic carriers and diagnostic tools. This approach utilized vari-

Fig. (7). 3 in 1 nanosystem can be constructed from metal or po-

lymeric FNPs that contains encapsulated drug, targeting ligand and

diagnostic agent through click chemistry or physical adsorption.


ous types of materials and their functionalization and con-nects the molecular mechanisms involved in physiology to drug targets and other biomedical applications such as imag-ing and tissue engineering. In addition, the fusion of func-tional groups to NPs allows for the development of multi-modality therapeutic strategies to integrate drug targeting, cancer therapy, diagnostics and tissue engineering. The work that has been conducted in this field so far has provided a better understanding of FNPs systems and has advanced the realization of bringing innovative multifunctional nanocarri-ers consisting targeting molecules, therapeutics, diagnosing tool to patients faster. A model of the FNPs 3in 1 nanosys-tem is shown in Fig. (7). Fabrication of the three in one FNPs nanosystem for therapy, targeting and imaging, can be achieved by producing NPs with the appropriate therapeutic, targeting ligand and imaging agent.

ACKNOWLEDGEMENTS

This work was supported by Kyungwon University re-search fund in 2010 and Grant No. 10032112 from the Re-gional Technology Innovation Program of the Ministry of Knowledge Economy. This work was also supported by GRRC program of Gyeonggi province [2009-B02, Devel-opment biodevice using DNA tile structure].

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Received: July 29, 2010 Revised: October 12, 2010 Accepted: October 14, 2010

R Subbiah Et Al_Curr Med Chem

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