Advanced Drug Delivery Reviews 60 (2008) 13071315

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Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Gold nanoparticles in delivery applications

Partha Ghosh, Gang Han, Mrinmoy De, Chae Kyu Kim, Vincent M. Rotello
Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, MA, 01003, USA

A R T I C L E

I N F O

A B S T R A C T
Gold nanoparticles (AuNPs) provide non-toxic carriers for drug and gene delivery applications. With these systems, the gold core imparts stability to the assembly, while the monolayer allows tuning of surface properties such as charge and hydrophobicity. An additional attractive feature of AuNPs is their interaction with thiols, providing an effective and selective means of controlled intracellular release. 2008 Elsevier B.V. All rights reserved.

Article history: Received 12 January 2008 Accepted 12 March 2008 Available online 10 April 2008 Keywords: Gold Delivery DNA Drug delivery Glutathione Nanoparticles Self-assembled monolayer Photochemistry Release

Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . Drug delivery using gold nanoparticles . . . . . . . . . . . . . . . . . . . . 3.1. Glutathione-mediated release of small molecules . . . . . . . . . . . . 3.2. Release of nitric oxide and singlet oxygen from gold nanoparticles . . . . 4. Gold nanoparticles for delivery of biomolecules . . . . . . . . . . . . . . . . 4.1. Gold nanoparticles for nucleic acids delivery via non-covalent conjugation 4.2. Gold nanoparticles for nucleic acid delivery by covalent linking . . . . . 4.3. Functionalized gold nanoparticles for protein delivery . . . . . . . . . . 5. Photothermal effect of gold nanoparticles in therapy . . . . . . . . . . . . . . 6. Gold nanoparticle targeting in vivo . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307 1308 1308 1308 1309 1311 1311 1313 1313 1313 1314 1314 1314 1314

1. Introduction Nanocarriers have provided a novel platform for target-specic delivery of therapeutic agents [1]. Over the past decade, several
This review is part of the Advanced Drug Delivery Reviews theme issue on Inorganic Nanoparticles in Drug Delivery. Corresponding author. Tel.: +1 413 545 2058; fax: +1 413 545 4490. E-mail address: rotello@chem.umass.edu (V.M. Rotello). 0169-409X/$ see front matter 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2008.03.016

delivery vehicles have been designed based on different nanomaterials, such as polymers [2], dendrimers [3], liposomes [4], nanotubes [5], and nanorods [6]. Gold nanoparticles (GNPs) have recently emerged as an attractive candidate for delivery of various payloads into their targets [7,8]. The payloads could be small drug molecules or large biomolecules, like proteins, DNA, or RNA (vide post). Efcient release of these therapeutic agents is a prerequisite for effective therapy. The release could be triggered by internal (e.g. glutathione (GSH) [9], or pH [10]) or external (e.g. light [11]) stimuli. Signicantly

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Table 1 Synthetic methods and capping agents for GNPs of varying core size Core size (d) 12 nm 1.55 nm Synthetic methods Reduction of AuCl(PPh3) with diborane or sodium borohydride Biphasic reduction of HAuCl4 by sodium borohydride in the presence of thiol capping agents Reduction of HAuCl4 with sodium citrate in water Capping agents Phosphine Alkanethiol References [16] [17,18]

level within therapeutic window. For example, a gold nanoparticle with 2 nm core diameter could be, in principle, conjugated with 100 molecules to available ligands (n = 108) in the monolayer [31]. Zubarev et al. have recently succeeded in coupling of 70 molecules of paclitaxel, a chemotherapeutic drug, to a GNP with 2 nm core diameter [32]. 3.1. Glutathione-mediated release of small molecules

10150 nm

Citrate

[1921]

the internal stimuli operate in a biologically control manner, whereas the external stimuli provide spatio-temporal control over the release. Gold nanoparticles exploit their unique chemical and physical properties for transporting and unloading the pharmaceuticals. First, the gold core is essentially inert and non-toxic [12]. A second advantage is their ease of synthesis; monodisperse nanoparticles can be formed with core sizes ranging from 1 nm to 150 nm (Table 1). Further versatility is imparted by their ready functionalization, generally through thiol linkages (vide post). Moreover, their photophysical properties could trigger drug release at remote place [13]. Several reviews describing nanoparticlebiomacromolecule interactions have recently been published, generally focusing on biosensing [14] and diagnostic [15] applications. This review will focus on drug, gene, and protein delivery using GNPs (Fig. 1). 2. Synthesis of gold nanoparticles Signicant efforts have been devoted over the past forty years to the fabrication of GNPs with monodispersity and controlled size. GNPs with varying core sizes are prepared by the reduction of gold salts in the presence of appropriate stabilizing agents that prevent particle agglomeration. Some common synthetic methods of coreshell GNPs are summarized in Table 1. Several research groups have fabricated delivery systems based on GNPs bearing functional moieties, which are anchored with thiollinkers, in their monolayers. A wide variety of monolayer protected clusters (MPCs) can be formed rapidly and in scalable fashion using the one-pot protocol developed by Schiffrin et al. in 1994 (Scheme 1) [17]. In this preparation, AuCl 4 salts are reduced with NaBH4 in the presence of the desired thiol capping ligand or ligands. The core size of the particles can be varied from 1.5 nm to 6 nm by varying the thiol gold stoichiometry. The functional diversity of MPCs can be extended through the formation of mixed monolayer protected clusters (MMPCs) that can be synthesized directly or through post-functionalization of MPCs. A versatile method for the creation of MMPCs is the place-exchange reaction developed by Murray (Scheme 1) [18]. In this protocol, foreign thiols displace the native ligands of MPCs in an equilibrium process. Taken together, the control of monolayer structure provided by nanoparticle synthesis, place displacement, and other postsynthetic modication methods [22] can be used to display a wide range of functionality at the particle surface, including biocompatible oligo(ethylene glycol) (OEG) and poly(ethylene glycol) (PEG) moieties [2330]. One obvious benet of these combined methodologies is that they are highly amenable to divergent synthesis, an important aspect in the creation of delivery vehicles. 3. Drug delivery using gold nanoparticles Drug delivery systems (DDSs) provide positive attributes to a free drug by improving solubility, in vivo stability, and biodistribution. They can also alter unfavorable pharmacokinetics of some free drugs. Moreover, huge loading of pharmaceuticals on DDSs can render drug reservoirs for controlled and sustained release to maintain the drug

GSH-mediated release represents an alternative non-enzymatic strategy for the selective intracellular activation of prodrugs. This methodology relies on the dramatic differential in intracellular GSH concentration (110 mM) [33,34] versus extracellular thiol levels [35], where the predominant thiols in blood plasma are glutathione (2 M) and cysteine (8 M) [36]. Current methodologies rely on disulde linkages between the drugs and carriers [3742]. While this approach can be effective, including an example currently in the clinic [37], it is difcult to tune the reactivity of the disulde linkage. Additionally, thioldisulde exchange can occur with surface cysteines of proteins in the bloodstream, potentially creating proteincarrier conjugates with altered bioavailability and pharmacokinetic proles. We expect our nanoparticles to be resistant to exchange with proteins due to the steric shielding of the goldthiol interface. In recent studies, we have demonstrated cellular delivery and GSHmediated release of a hydrophobic dye (BODIPY), as a model of hydrophobic drugs, using functionalized gold nanoparticles (fGNPs) [9]. The particles (core d = 2 nm) featured a mixed monolayer composed of tetra(ethylene glycol)ylated cationic ligands (TTMA) and uorogenic ligands (HSBDP) (Fig. 2a). The cationic nature facilitates the crossing of cell-membrane barrier, and the uorophore probes possible drug release mechanism. BODIPY-conjugated GNPs are nonuorescent as the gold core quenches uorescence via energy and/or electron transfer processes [43,44]. The uorescence signal emanates upon triggering the GNPs with GSH in cuvette, or cellular thiols in human liver cells (Hep G2) (Fig. 2b). Controlled release of the dye was veried by treating mouse embryonic broblast cells (MEF, having 50% lower intracellular GSH levels than Hep G2) with varying concentration of glutathione monoester (GSH-OEt: 0, 5 and 20 mM)

Fig. 1. Various applications of gold nanoparticles in therapy.

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Scheme 1. Formation of MPCs using the Schiffrin reaction and MMPCs using the Murray's place-exchange reaction.

Fig. 2. a) A schematic depiction of the GSH-mediated payload release via place-exchange reaction. b) Bright eld and uorescence micrographs of human Hep G2 cells after incubation with GNPs for 96 h. c) Fluorescence images showing dose-dependent release of the payloads.

(Fig. 2c). GSH-OEt is rapidly internalized into cells and hydrolyzed to GSH, and hence transiently manipulates cellular GSH levels. 3.2. Release of nitric oxide and singlet oxygen from gold nanoparticles GNPs could possibly be employed in delivery of diatomic therapeutic agents, like singlet oxygen, or nitric oxide. Singlet oxygen (1O2), a cytotoxic species, involves in photodynamic therapy of cancer [45]. Russell and coworkers decorated the surface of MPCs with phthalocya-

nines (PCs), a photosensitizer to generate singlet oxygen with good quantum yield (Fig. 3a) [46]. The quantum yield of free PCs was increased by 50% (from 0.45 to 0.65) upon conjugation to MPCs. Moreover, the conjugation promoted solubility of hydrophobic PCs in polar solvent (from toluene to ethanol). Nitric oxide (NO) regulates multiple cellular processes including angiogenesis, vasodilation, and the immune response [47]. Controlled release of NO could be an effective therapy for hypoxic respiratory failure associated with pulmonary hypertension. Schoensch et al. demonstrated

Fig. 3. a) Phthalocyanine-functionalized gold nanoparticles for generation of singlet oxygen. b) A nanocontainer for NO storage.

Fig. 4. a) MMPCs used for transfection. b)Transfection of -galactosidase mediated by formation of various MMPCDNA complexes at 2200:1 nanoparticle/DNA ratio. c) Transfection with MMPCs 5, 6, 7 (2200:1 nanoparticle/DNA ratio) and PEI (60 kDa). All transfections were performed in the presence of chlorquine (100 M) and serum (10%).

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Fig. 5. (a) Conjugation of nanoparticle with branched 2 kDa polyethylenimine (PEI2). (b) Incorporation of PEI2 onto nanoparticles increases the transfection efciency. Addition of dodecyl-PEI2 to the conjugate further increases the transfection efciency. The numbers in the parentheses indicate the ratio of PEI nitrogen to DNA phosphate. (c) Cyclodextrinfunctionalized cationic nanoparticles used for transfection.

Fig. 6. a) A schematic illustration for nuclear delivery of DNA using photolabile nanoparticles. b) Light-induced surface transformation of NP-PC. c) Fluorescence and bright eld microscopy images after photorelease of DNA from the NP-PCDNA complex. To clarify the overlap of F-DNA and nuclear stain DAPI; green channel (Fluorescein) and blue channel (DAPI) are depicted with red and yellow, respectively. d) Confocal micrographs illustrating the accumulation of photo-released DNA inside the nucleus. Panels 1, 2, 3 and 4 show four consecutive slices of middle sections of z-series confocal images (interval= 1.0 m). (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)

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Fig. 7. a) Antisense DNA modied gold nanoparticle (ASNP). b) Before and c) after incubation with antisense DNA functionalized nanoparticles for EGFP-expressing C166 cells. Reprinted with permission from Ref. [63].

that NO can be efciently stored by covalent linking with polyaminestabilized MPCs via formation of acid labile N-diazeniumdiolate (Fig. 3b) [10]. They showed effective release of NO from the water-soluble nanocontainers in acidic condition (pH=3). pH-responsive materials are applicable for drug delivery due to presence of mild acidic environment inside inammatory and tumor tissues (pH 6.8), or cellular vesicles like endosomes (pH 5.56) and lysosomes (pH 4.55.0) [4850]. 4. Gold nanoparticles for delivery of biomolecules Gold nanoparticles are capable of delivering large biomolecules, without restricting themselves as carriers of only small molecular drugs. Tunable size and functionality make them a useful scaffold for efcient recognition and delivery of biomolecules. They have shown the success in delivery of peptides, proteins, or nucleic acids like DNA or RNA.

4.1. Gold nanoparticles for nucleic acids delivery via non-covalent conjugation Gene therapy presents an ideal strategy for the treatment of genetic as well as acquired diseases [51]. Viruses provide a logical vehicle for gene therapy, and have been shown to be highly efcient [52]. Viruses have nonetheless raised many safety concerns arising from unpredictable cytotoxicity and immune responses [53]. Synthetic DNA delivery systems have overcome these limitations. However, current non-viral gene delivery systems suffer from less efciency. The vectors encounter numerous barriers between the site of administration and localization in the cell nucleus [54]. The effective delivery vehicles need to provide efcient protection of nucleic acid from degradation by nucleases, efcient cell entry, and release of the nucleic acid in functional form in the nucleus [55]. GNPs provide attractive candidates for gene delivery. They can be made quite small to provide a high surface-to-volume ratio, maximizing the payload/carrier ratio. Perhaps equally important, the monolayer coverage of MPCs and MMPCs systems allow tuning of the charge and hydrophobicity to maximize transfection efciency while

Fig. 8. Schematic representation of GSH-mediated disruption of nanoparticle-gal protein interactions.

Fig. 9. Photothermal effect of gold nanoparticles for releasing encapsulated materials. a) Preparation of a microcapsule by layer-by-layer process, b) Encapsulation of therapeutic agents, c) Doping of GNPs in the capsuleshells, d) Rupture of the shell upon light irradiation.

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Fig. 10. A schematic illustration of drug delivery via active and passive targeting, solid and dotted line respectively.

minimizing toxicity. We have shown in our earlier studies that gold nanoparticles functionalized with cationic quaternary ammonium groups (a) bind plasmid DNA through electrostatic interactions [56],

(b) protect DNA from enzymatic digestion [57] and (c) release the bound DNA by GSH treatment in cuvette [58]. These non-covalent DNAnanoparticle conjugates provide an effective means of gene

Fig.11. a) The functionalization of gold nanoparticles with PEG and a targeting ligand (galactose). Amount of different nanoparticles in b) blood and c) liver. Reprinted with permission from Ref. [73].

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nium salt as endgroup (Fig. 6b). After complexation of the particle with DNA, near-UV irradiation cleaves the nitrobenzyl linkage creating an anionic carboxylate group and releasing the DNA. In vitro studies using a T7 RNA polymerase assay demonstrated that DNA transcription was restored upon UV irradiation. Cell culture studies indicated that the particleDNA complexes were effectively taken up by cells. Release of FITC-labeled DNA upon irradiation was established by observation of bright uorescence inside the cells (Fig. 6c). Moreover, a high degree of nuclear localization was observed for the released DNA (Fig. 6d). 4.2. Gold nanoparticles for nucleic acid delivery by covalent linking Nucleic acid strands could be easily modied with thiols (SH) for grafting onto nanoparticles. Nagasaki and coworkers conjugated thiolated siRNA (SH-siRNA) with gold nanoparticles for cellular delivery [62]. RNA-modied particles were coated with poly (ethylene glycol)-block-poly(2-(N,N-dimethylamino)ethyl methacrylate) copolymer to enhance cellular internalization. These smart delivery systems were effective for gene silencing in HuH-7 cells. Notably, RNAi activity has revolutionized the gene therapy strategy in twenty rst century. In general, polycationic materials are used for condensing DNA and transporting it inside the cell. However, a breakthrough emerged in 2006 when Mirkin et al. reported cellular internalization of oligonucleotide-modied nanoparticles (DNA-NPs), carrying large negative surface potential (Fig. 7) [63]. These particles were stable against enzymatic digestion. Incubation of cells with nanoparticles conjugated with uorophore-labeled DNA revealed efcient uptake of the particles. In this system, antisense DNA hybridized with the particle controlled the protein expression. This was demonstrated using EGFPexpressing C166 with antisense DNA functionalized nanoparticles, providing a reduction of uorescence intensity in cells. Very recently, they have found out the mechanism of cellular uptake of DNA-NP the endocytosis process is initiated by adsorption of numerous serum proteins onto particle's surface [64].
Fig. 12. a) Change in tumor volume over days after treatment with TNF and CYT-6091. b) In vivo delivery of TNFgold nanoparticle conjugate CYT-6091. Reprinted with permission from Ref. [8].

4.3. Functionalized gold nanoparticles for protein delivery Gold nanoparticles can likewise be nanocarriers of peptides and proteins of interest. Rotello et al. have reported that cationic tetraalkyl ammonium functionalized GNPs recognize the surface of an anionic protein through complementary electrostatic interaction and inhibit its activity (Fig. 8) [65]. The activity was recovered due to release of free protein by treating the proteinparticle complex with GSH, showing GNPs as potential protein transporters. In a recent study, Pokharkar, Sastry and coworkers have demonstrated functionalized gold nanoparticles as carriers of insulin [66]. The particles were stabilized by chitosan, a non-toxic biopolymer. Chitosan-coated particles strongly adsorb insulin on their surface, and are effective for transmucosal delivery of insulin. 5. Photothermal effect of gold nanoparticles in therapy In addition to the surface chemistry of GNPs, their physical properties could be exploited for delivery applications [67]. GNPs cause local heating when they are irradiated with light in the water window (800 nm1200 nm). El-Sayed et al. have recently reported about potential use of GNPs in photothermal destruction of tumors [68]. Citrate-stabilized GNPs (core d = 30 nm) were coated with antiEGFR (epidermal growth factor receptor) to target HSC3 cancer cells (human oral squamous cell carcinoma). The use of GNPs enhanced the efcacy of photothermal therapy by 20 times. In another approach, optically responsive delivery systems have been designed by incorporation of Au nanospheres into the shells of capsules. Caruso et al. prepared microcapsules via layer-by-layer (LBL)

delivery in mammalian 293T cells [59] (Fig. 4). Signicantly, amphiphilic particles provided superior transfection vectors, indicating that hydrophobicity of the nanoparticles improves the efciency of cellular uptake and/or the subsequent release of the DNA from the endosomal vesicle. This optimized nanoparticle was 8-fold more efcient than polyethyleneimine (PEI). Later on, Klibanov et al. functionalized gold nanoparticles with branched polyethylenimine (PEI, 2 kDa) to provide hybrid AuNP-polymer transfection vectors (Fig. 5a) [60]. They determined that the transfection efciency into monkey kidney (Cos-7) cells varied with the PEI:gold molar ratio in the conjugates. At the optimized ratio, the conjugates were 12fold more potent than the polymer itself (Fig. 5b). Similar to the above studies, their research indicated that increasing the hydrophobicity of the transfection agent enhances cellular internalization and hence transfection efciency. Recently, Liu et al. fabricated effective binders of DNA by anchoring -cyclodextrin on the periphery of oligo(ethylenediamino)modied gold nanoparticles (OEA-CD-NP) (Fig. 5c) [61]. They have demonstrated the ability of OEA-CD-NP to deliver plasmid DNA into breast cancer cells (MCF-7). Rotello et al. have recently reported photochemical uncaging of the loaded DNA on surface of the nanoparticles (Fig. 6a) [11]. A photolabile nanoparticle was designed to switch the nature of surface from cationic to anionic upon irradiation. This particle was tailored with a photocleavable o-nitrobenzyl ester linker and a quaternary ammo-

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technique to encapsulate macromolecules like uorescein-labeled dextrans (Fig. 9) [69]. The capsuleshells were doped with GNPs, which response against near infra red (NIR) light. FITC-dextran was released upon laser (1064 nm) treatment due to rupture of the shell. Skirtach, Parak and coworkers have extended this strategy to deliver encapsulated materials from polyelectrolyte-multilayer capsules inside living cancer cells [13]. 6. Gold nanoparticle targeting in vivo For in vivo applications, the goal of nanocarriers is to arrive at the diseased tissues after administration into circulatory system. Two approaches have been developed for targeting namely passive and active targeting (Fig. 10) [70,71]. Passive targeting depends on homing of the vectors in unhealthy tissues due to extravasation through leaky (gaps 600 nm) blood vessel. An important aspect of carrier systems in the 510 nm scale is their ability to take advantage of the enhanced permeation and retention (EPR) effect (Fig. 1) [72]. On the other hand, active targeting presents ligands on the carrier surface for specic recognition by cell surface receptors. The ligands could be small molecules, peptides or proteins. Combination of both types of targeting will render an ideal carrier for in vivo delivery. Nanocarriers suffer from non-specic uptake and potential degradation in macrophages. Therefore, targeting is crucial for maximizing drug efcacy while minimizing side effects. Pun et al. have recently reported how different physicochemical properties, such as size, PEGylation, or the ligand, regulate non-specic versus target-specic uptake [73]. They used gold nanoparticles with or without PEGylation (PEG5000) named PEG-NP or unmodied NP, respectively of varying sizes (50, 80, 100, or 150 nm) (Fig. 11a). Galactose-PEG-thiols were grafted onto PEG-NPs to provide Gal-PEGNP for active targeting of liver, more specically hepatocytes. Samples were collected from blood and liver after 2 h of injection. Furthermore, hepatocytes and nonparenchymal cells (NPCs) of the liver were analyzed. The results could be summarized as follows: (a) PEGylation increases blood circulation life-time (comparing unmodied NP and PEG-NP in Fig. 11b), (b) Galactose, a ligand, facilitates ltration of Gal-PEG-NPs into liver (comparing PEG-NP and Gal-PEGNP in Fig. 11b), and (c) the ligand renders cell-specic targeting of hepatocytes, particularly, for 50 nm particles (from Gal-PEG-NP in Fig. 11c). Interestingly, Chan et al. reported that gold nanospheres of 50 nm in diameter are internalized by mammalian cells at a faster and higher rate compare to other nanoparticles (core d = 14, 30, 74, or 100 nm) [74]. They have also revealed that the transferrin-coated particles enter into cells possibly via clathrin-mediated endocytosis pathway [75]. Two targeting molecules, folic acid (FA) and methotrexate (MTX), are specically recognized by folate receptors that are overexpressed on the surfaces of many tumor cells. Andres and coworkers have recently demonstrated the selective delivery of FA-nanoparticles by folate receptor-positive KB cells [76]. In their studies, folic acid was conjugated onto gold nanoparticle (d = 10 nm) with PEG spacer. The particles were effectively internalized by KB cells, but little cellular uptake was detected in WI cells that do not overexpress folate receptor. Besides a targeting moiety, methotrexate could function as an anticancer drug. Wu, Shiau and coworkers have demonstrated that MTXGNP conjugate inhibits tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2) [77]. Gold nanoparticles are not only useful for cell-specic targeting, but also for localization into desired organelles. Fuented et al. decorated gold nanoparticles with TAT peptides, a nuclear localization signal, for translocating them into nucleus [78]. Paciotti et al. carried out in vivo study to investigate the therapeutic effect of PEGylated gold colloids (cAu-PEG-TNF) with adsorbed protein (tumor necrosis factor, TNF) [7]. When cAu-PEG-TNF were injected intravenously into mice, they were largely accumulated in MC-38

colon carcinoma tumors compared to liver, spleen, or other healthy organs. TNF provided both targeting and therapeutic action via killing the targeted cells. Importantly, the particles were more effective at diminishing tumor mass than free TNF. Recent studies by this group have demonstrated enhanced tumor therapy by grafting paclitaxel, an anticancer drug, onto cAu-PEG-TNF (Fig. 12) [8]. 7. Conclusions Gold nanoparticles have emerged as a promising scaffold for drug and gene delivery that provide a useful complement to more traditional delivery vehicles. Their combination of low inherent toxicity, high surface area and tunable stability provides them with unique attributes that should enable new delivery strategies. The key issue that needs to be addressed is the engineering of the particle surface for optimizing properties such as bioavailability and nonimmunogenicity. Acknowledgements This research was supported by the NIH (GM077173) and the NSF Center for Hierarchical Manufacturing at the University of Massachusetts (NSEC, DMI-0531171). References
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