Review Article Design Of Nanoparticle-Based Carriers For Targeted Drug .

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Hindawi Publishing CorporationJournal of NanomaterialsVolume 2016, Article ID 1087250, 15 pages ArticleDesign of Nanoparticle-Based Carriers forTargeted Drug DeliveryXiaojiao Yu,1 Ian Trase,1 Muqing Ren,2 Kayla Duval,1 Xing Guo,1 and Zi Chen11Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USADepartment of Chemical Physics, University of Science and Technology of China, Hefei, Anhui 230026, China2Correspondence should be addressed to Zi Chen; zi.chen@dartmouth.eduReceived 8 December 2015; Revised 29 March 2016; Accepted 3 April 2016Academic Editor: Martin KrögerCopyright 2016 Xiaojiao Yu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designedin order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understandexisting ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticleand cancer cells. In this paper, we provide an overview of three different targeted drug delivery methods (passive targeting, activetargeting, and physical targeting) and compare methods of action, advantages, limitations, and the current stages of research. Forthe most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computationalsimulations and models on nanoparticle-based drug delivery.1. IntroductionNanoparticles (NPs) often exhibit different magnetic, thermal, optical, and electrical properties due to their high surfacearea and limited quantum mechanical effects [1]. NPs areoften developed and used as drug carriers, as they can deliverchemotherapeutics targeted to the tumor tissue withoutdamaging normal organs (Figure 1). The ideal NP carriersshould be biodegradable, stable, nonimmunogenic, easy tofabricate, cost-effective, and able to release their payloadsonly at the target site [2].Medical NPs are often manufactured with a guidedbottom-up method, in which engineered macromolecularcomponents are guided by external stimuli to interact witheach other and self-assemble into complex structures thatotherwise would not be possible [3]. Drugs can be eitherencapsulated within the nanoparticle or attached to thesurface.A typical drug delivery nanoparticle starts with ananoplatform class, which include liposomes, polymericmicelles, drug conjugated polymers, and dendrimers [4–7]. There are three main methods to transport drug-loadednanoparticles to diseased sites: passive targeting, activetargeting, and physical targeting. Passive targeting worksthrough the increased permeability and retention (EPR)effect, which makes tumor cells preferentially absorb NPsized bodies [8, 9]. In active targeting, NPs are functionalizedwith ligands such as antibodies, proteins, and peptides [10],which interact with receptors overexpressed at the target site[11]. Physical targeting uses external sources or fields to guideNPs to the target site and to control the release process,for example, in photothermal and magnetic hyperthermiatherapy. For all targeting types, drug release can be triggeredby a change in pH, temperature, or a combination of both.In order to design an effective NP, one needs to understand the combinatorial effects of size, shape, surface chemistry, patient-specific information, and other parameters.Optimizing all of these parameters through experiments isboth time- and resource-intensive, and so computationalmodeling is used to shrink this possibility space. Simulationshave been used to model the continuum of NP transportand the quantum mechanical interactions of ligand receptors.Mesoscale modeling and Monte Carlo simulations are alsooften used when certain values are uncertain [12].The aim of this paper is to review fabrication methods for the most common nanoparticle types (specifically

2Journal of NanomaterialsTumorTumorFree drugDrug-loaded NPs(a)(b)Figure 1: Schematic contrast of drug biodistribution after injection of free drug (a) and drug-loaded NPs (b).self-assembly), targeted drug delivery processes, and thecurrent state of NP computational modeling. Directions forfuture research are also discussed.2. Self-Assembled Nanoparticles asDelivery VehiclesMedical nanoparticles, despite their name, are far from thesmallest things that scientists and engineers work with.Rather, they occupy a manufacturing blind spot locatedbetween large and small structures. Objects and materialswith features at, and larger than, the microscale are now readily fabricated through “top-down” approaches like lithography and precision machining. Objects smaller than nanoparticles are generally easily synthesized through “bottom-up”methods in which individual chemicals essentially assemblethemselves under the influence of intermolecular forces.Nanoparticles are too large and complex to be made bysimply mixing their molecular components in a test tubebut much too small to be assembled with even the highest precision lithographic device. The solution is a guidedbottom-up approach, in which macromolecular componentsare engineered to interact with each other and often external

Journal of Nanomaterials3LiposomeMicelleFigure 2: Schematic of two types of amphiphilic nanoparticles, liposomes and micelles. Liposomes have a double layer and a hydrophiliccore, while the core of micelles is hydrophobic.stimuli fields and self-assemble into structures more complexthan would otherwise be possible [3].While there are many types of self-assembled nanoparticles, the most studied can broadly be sorted by structure.Below is an introduction, with examples, to amphiphilic NPs(the most common type of drug carrying NP), followed by abrief explanation of other novel NP structures: dendrimers,polyrotaxanes, functionalized carbon nanotubes, graphene,and metal solid-core nanoparticles. It is important to notethat all of these NPs can be functionalized to actively targetspecific sites in and on tumor cells.2.1. Amphiphilic Nanoparticles. The earliest drug NPs werebiomimetic in nature, mimicking the micelles and liposomesalready present in the body. These NPs contain macromolecules with both hydrophobic and hydrophilic regions.In an aqueous environment such as blood or cellular fluid,the hydrophobic regions will cluster together in order tobe shielded from the surrounding polar water, forming amicelle. Synthetic micelles have hydrophobic cores, whilemore complex amphiphiles can form full liposomes with adouble-layered macromolecular wall and a hydrophilic corewith the same properties as or different properties from thesurrounding fluid (Figure 2). Drugs can be captured eitherin the core or on the surface of these particles, dependingon their hydrophobicity. In either case, the drug is shieldedfrom removal by the immune system and from other in vivohazards.An early example of micelle-forming particles involvedpoly(ethylene oxide)-poly(aspartic acid) (PEO-PAA) blockcopolymers [21]. These polymers were used to create a selfassembling micelle containing the chemotherapy drug doxorubicin (DOX). DOX is commonly used to test the efficacyof self-assembling carriers and comes in both hydrophobicand hydrophilic HCl formulations—it can be assumed to behydrophobic unless otherwise stated. In this case, DOX wasbound to the hydrophobic PAA polymer in organic solventand then pushed through a membrane into an aqueous solution, a technique known variously as membrane dialysis ordiafiltration. This transition from hydrophobic to hydrophilicsolution induces the formation of micelles and leaves DOXencapsulated at the PAA center. The resulting nanoparticlewas extremely soluble and stable in water, increasing the halflife of the payload drug.A similar experiment was carried out with an amphiphilicpullulan acetate polymer [22]. Cancer cells have been shownto overexpress vitamin H, so the polymer was functionalizedwith it in order to actively target these cancer cells. After DOXwas loaded into the micelles using membrane dialysis, theauthors found that the amount of vitamin H expressed onthe surface of the nanoparticle correlated with its uptake bycancer cells, indicating successful active targeting.More complex micelles can be engineered to releasetheir payloads in response to external stimulation. Bae etal. [23] had designed pH-sensitive nanoparticle carrierswhich follows previous reports on poly(ethylene glycol)poly(aspartate-hydrazone) copolymers. DOX was bound tothe hydrazone group and micelles were again formed throughmembrane dialysis. Hydrazone bonds are easily cleaved inacidic conditions, so this micelle was designed to exposeDOX in response to low pH. Micelles are taken up bycells through endocytosis and subsequently engulfed bylysosomes, which have a pH of around 5 and thus trigger drugrelease. The authors found that DOX concentration decreasedas a function of pH, with around 30% of the drug released ata pH of 5 and the entire payload released at lower pH.A particularly interesting trigger-based nanoparticlewas created by combining the pH responsive polymerpoly(acrylic acid) (PAA) with the heat sensitive poly(Nisopropylacrylamide) (PNIPAM) [24]. PNIPAM becomeshydrophobic above its lower critical solution temperatureof around 32 C, while PAA becomes hydrophobic at a pH

4below 4.8. The copolymer will thus form a micelle with aPNIPAM core at high temperature and pH but flip to a PAAcore at low temperature and pH. PAA also binds to DOX inaqueous solution, eliminating the need for organic solventsor membrane dialysis. When it binds at low temperatureand high pH, the PAA-DOX complex becomes hydrophobicand forms micelles. This nanoparticle was shown to exhibitdrug release with both an increase in temperature (whichcauses the micelle to flip inside-out and expose DOX tothe environment) and a drop in pH (which causes PAA toprotonate and release the less positive DOX). PNIPAM hasalso been used to synthesize nanoparticles that can shrink involume in response to temperature [25].Polymer nanoparticles have also been made with hybridpolymer-lipid amphiphiles, which allow for a broader rangeof potential polymers. This system was used in a nanoparticleable to hold both drugs and DNA using a cationic core-shellsystem [26]. The main polymer chain is hydrophilic poly(Nmethyldietheneamine sebacate) (PMDS) grafted with thehydrophobic N-(2-bromoethyl) carbamoyl cholesterol lipidto form an amphiphilic copolymer. The antitumor drug paclitaxel (PTX) was encapsulated through membrane dialysis,and luciferase-coding DNA was bound to the nanoparticlein order to detect fluorescence. It was found that cancercells successfully expressed luciferase, indicating successfulendocytosis. Lipids can also be used as a molecular shield toincrease drug half-life in blood [27].It is also possible to change the chemistry of certain polymers to distort the resulting nanoparticle [28]. Micelles canbe created in a variety of nonspherical shapes using poly[oligo(ethylene glycol) methacrylate]-block-[poly(styrene)-copoly(vinyl benzaldehyde)] block polymers. The shape ofthe micelles changed from sphere to rod as the degree ofpolymerization for the P(ST-co-VBA) blocks increased. DOXwas able to be loaded into the micelles as normal.Huang et al. [29] designed a poly(lactide-co-glycolic acid)nanoparticle coated with sgc8 aptamer capable of carryingboth a hydrophobic and hydrophilic cancer drug. After selfassembly, hydrophilic DOX is located in the poly(ethyleneglycol) shell and hydrophobic paclitaxel is located in thePLGA core. The sgc8 aptamer causes the nanoparticle tobe internalized by cancer cells specifically, an example ofactive targeting. The authors show that the multidrug combowas more effective than either drug individually at reducingcell viability, and the addition of a second drug had aninsignificant effect on the viability of normal cells. It is alsopossible to use transferrin on the nanoparticles to increaseuptake by cancer cells [30].Xia et al. [31] designed silk-elastin protein polymernanoparticles. Silk-elastin-like proteins are synthetic genetically engineered proteins designed to mimic the properties ofboth silk and elastin. The proteins are temperature-dependentamphiphiles and will form micelles. In this case, it wasshown that DOX actually triggered micelle formation insome cases by increasing the hydrophobicity of the silk-endchains. The authors reason that this polymer and method ofself-assembly, since it is formed biologically in nonextremeenvironments, will generate fewer toxins and be a saferalternative to traditional methods.Journal of Nanomaterials2.2. Novel Nanoparticle Structures. An example of a novelnanoparticle structure is a dendrimer (Figure 3(d)), whichis a repeatedly branching nanostructure that mimics thestructure of tree branches and blood vessels [4]. This shapeis shown to both generate large surface areas and disperse asurface more evenly throughout the structure. Dendrimersare commonly made of poly(amidoamine) but can alsobe made from other polymers. It has been shown thatdendrimers can be used to target cancer cells with highaccuracy [32]. Li et al. reported a novel class of micellesmade of linear PEG and dendritic cholic acids (CA) blockcopolymers (called telodendrimers) [15]. By cross-linking theboronate esters at the core-shell interface, the stability ofthese micelles can be improved (Figure 4) [16]. As the crosslinking reactants, boronic acid and catechol were added to thepolymers through stepwise peptide chemistry.Rotaxanes are molecular linkages in which a cyclicmolecule encircles a dumbbell-shaped one—the cyclicmolecule can rotate but cannot slide off of the dumbbell. Polyrotaxanes (Figure 3(a)) can be a useful tool for drug delivery[33]. Liu et al. attached cyclic cyclodextrin to poly(ethyleneglycol) chains in order to form a nanoparticle. Hydrophobiccinnamic acid was attached to the ends of the PEG chains inorder to increase the space between the cyclodextrin rings,providing space for DOX to bind [33]. This system can alsobe used to transport the drug methotrexate [13].Dendrimers and rotaxanes are used primarily for drugdelivery, but the next three structures are also often usedin thermal therapy, where a localized temperature increaseis used to destroy a tumor. Graphene (Figure 3(b)) is asingle atom-thick hexagonal allotrope of carbon with novelelectrical, thermal, and mechanical properties. Because of itshigh surface area, it is useful as a drug carrier, and its structuremakes it efficient at converting infrared light into heat. It is,however, relatively toxic and must be stabilized and shieldedthrough the addition of polymers to its surface [14, 34].Carbon nanotubes (Figure 3(c)) are rolled tubes of graphenethat exhibit many of the same properties. Nanotubes havebeen used as hybrid drug carries, where the antitumor drugis released only in a specific site when bombarded with nearinfrared radiation and the NPs are heated up. This can help tolimit drug release to the tumor site and protect healthy tissue[35, 36].Metal-core nanoparticles (Figure 3(e)) can be usedphotothermally, like graphene and carbon nanotubes, butthey can also be used for magnetic hyperthermia, wherea magnetic NP oscillates and heats up in response to anexternal magnetic field. Most NPs are made of magnetite ormaghemite cores and are relatively biocompatible. Successfulclinical trials have also been done with a magnetic fluidcomposed of dispersed NPs in water [37].Oligopeptides have been extensively studied as nanocarriers due to their intrinsic pH sensitivity resulting fromamino acids. Mo et al. developed a liposome system basedon zwitterionic oligopeptide lipids as nanocarriers [38].The amino acid-based lipids, 1,5-dioctadecyl-l-glutamyl 2histidyl-hexahydrobenzoic acid (HHG2C18 ) and 1,5-distearylN-(N-𝛼-(4-mPEG2000) butanedione)-histidyl-l-glutamate(PEGHG2C18 ), have a multistage pH-response to first the

Journal of Nanomaterials5(a)(b)(c)(d)(e)Figure 3: Structures of novel nanoparticles. (a) Polyrotaxane NPs are assembled from cyclical molecules threaded around a long polymerchain. Hydrophilic ends are added to the chain in order to induce self-assembly. Drugs are then added to the finished NP. Adapted withpermission from [13]. (b) Graphene functionalized with shielding molecules and ligands. Adapted with permission from [14]. (c) Carbonnanotube schematic. (d) Dendrimer schematic. (e) Metal-core photothermal NP schematic.tumor microenvironmental pH (pH 6.8) and then the endo/lysosomal pH (pH 4.5).Supramolecular polymers have significant potentialapplication in drug delivery due to their reversible monomerto-polymer transitions. Figure 5 shows the molecular unitdesigned to form a supramolecular architecture [17]. Thepair is a peptide amphiphile monomer composed of threesegments: a biological signal-bearing sequence, an aminoacid-contained domain, and a hydrophobic alkyl tail. Thesemonomers can form a cylindrical aggregate where twisted𝛽 sheets (red) collapse through hydrophobic interactionsamong alkyl chains, resulting in high signal densities. Theblue regions represent water domains present in the assemblyinterior.2.3. Challenges in Nanoparticle Development. There are manychallenges that arise in the early and late stage development ofmedical nanoparticles that are either nonexistent or minimalin non-nanoparticle-based therapies [39]. The primary driverof these issues is the hierarchical and nonuniform nature ofnanoparticles, which means that a small change in a singleproperty can have outsized effects on the pharmacokineticsor therapeutic efficacy of the particle. As an example, onecommon issue is maintaining a narrow distribution of particle size. For most applications, a particle size under 200 nmis desirable. With a broad normal distribution of sizes, thismeans that often the average particle must be too small to beuseful in order to limit the number of particles over 200 nm. Amanufacturing process that ensures a narrow size distributionis thus desirable.In addition, many unique challenges can arise during thetrial and production stages of the nanoparticle. Oftentimes,a procedure for nanoparticle formation that works in a labsetting will not work in a factory, and the synthesis stepsmust be completely reworked. In a factory, the variation innanoparticle structure must be smaller, the yield must behigher, and the synthesis must be more sterile than what isacceptable in a lab. All of these things can make a particleunviable to produce even if it works. If a particle is sold,it must be shelf-stable, which means both that it will notdegrade in solution and that it will not clump over time,as nanoparticles often do. Finally, nanoparticles face extra

6Journal of NanomaterialsBCBCPEG 5000PEG 5000n nBBCPEG5k-L2 -(boronic acid)4 -CA8CPEG5k-L2 -catechol 4 -CA8NHOOBOORHNHydrophobicdye or drugMannitol and/oracidic pHSelf-assembleIn situ cross-linkFigure 4: Schematic representation of the disulfide cross-linked micelles formed by oxidization of self-assembled thiolated telodendrimerPEG5k -Cys4 -L8 -CA8 [15]. Schematic representation of the telodendrimer pair [PEG5k -(boronic acid or catechol)4 -CA8 ] and the resultingboronate cross-linked micelles (BCM) triggered by mannitol and/or acidic pH values [16].Supramolecular polymerMonomerNanofiberLipid tail𝛽-domainBiological signalFigure 5: Molecular representation of monomer and the corresponding supramolecular polymer formed after their aggregation throughspecific interactions [17].regulatory challenges as their toxicity is much more difficultto determine than that of a small molecule. This greatlyincreases the time and cost of clinical trials. These challengescombined mean that it is always prudent to consider questions of scalability and reproducibility even at the earlieststages of development to prevent failure at a later stage.3. Cancer Cell Targeted Drug Delivery3.1. Mechanisms of Targeted Cancer Cell Drug Delivery. Cancer cells are otherwise normal cells with unique mutationsin genes regulating growth, which cause them to divideuncontrollably and give them the ability to metastasize [40].Cancer cells successfully compete with normal cells foroxygen, glucose, and amino acids for division and growth,but a tumor can only grow to about 2 mm3 without formingblood vessels (angiogenesis) [41–43]. There are more thanone hundred types of cancer, more than 85% of which aresolid [43]. Current treatment includes surgery, radiotherapy,chemotherapy, hormone therapy, and immunotherapy [43].However, the inability of drugs to specifically target cancercells hinders most treatment [2, 44, 45]. It is often quicker

Journal of Nanomaterials7Endothelial cellNormal cellRed blood cellBlood vesselTumor cellDrug-loaded NPsFigure 6: Schematic illustration of enhanced permeation and retention (EPR) effect.and cheaper to design a more effective way to better targetan existing drug than to develop an entirely new one. Drugdelivery targeting is classified as passive, active, or physicaland can target organs, cells, or organelles. Organelle targetingis an especially promising field of research, as many cancersspecifically affect a single one, and certain organelles providealternative paths for drug localization.3.2. Passive Targeting Nanocarrier Systems. Drugs deliveredintravenously tend to evenly disperse throughout the body.However, tumor cells tend to take up particles of a certain sizeto a greater degree than healthy cells due to a combinationof leaky tumor blood vessels and faulty particle screening.This is known as the enhanced permeation and retention(EPR) effect (Figure 6) and is the mechanism behind passivetargeting [46].The EPR effect is influenced by NP properties includingparticle size, shape, and surface charge, and it in turn influences circulation time, penetration speed, and intracellularinternalization [47, 48]. For example, phagocytic cells facilitate larger particle uptake, while nonphagocytic cells favorthe uptake of smaller particles [49]. It has been consistentlyshown that PEGylated nanoparticles reduce plasma proteinadsorption on their surface and reduce hepatic filtrationwhen their size is smaller than 100 nm [50]. The nanoparticlesurface properties could play a central role in blood circulation and subsequent cellular internalization [48, 51]. NPs witha negative surface charge will circulate longer in the blood,but positively charged NPs are more readily taken up bycancer cells (which have negative surface charge) [8–10, 52–54]. In order to clarify the influence of shape on the cellularuptake of PEGylated NPs, Li et al. performed large-scalemolecular simulations to study different NP geometries withidentical surface area, ligand-receptor interaction strength,and PEG grafting density (Figure 7) [20]. They found thatspheres exhibited the fastest internalization rate, followed bycubes, while rods and disks were the slowest.Delivery platforms include liposomes [5], polymericmicelles [6, 7], targeted polymer drug conjugates [4], anddendrites. They all consist of macromolecule collections inwhich drugs are dissolved, entrapped, or conjugated to thesurface [55]. Several liposomal drug delivery systems have

8Journal of NanomaterialsSphereRodCubeDisk(a)(b)Figure 7: Different shapes of NPs: sphere, rod, cube, and disk. (a) shows the transmission electron microscopy images of these NPs [18, 19].(b) shows the PEGylated NPs with grafting density 1.6 chains per nm2 in molecular simulations [20].received clinical approval, including ones for doxorubicinand daunorubicin. An albumin-bound nanoparticle carryingpaclitaxel, Abraxane, was also approved by the FDA for breastcancer treatment [56].Despite the EPR effect, more than 95% of passivelytargeted NPs fail to reach the tumor when administeredintravenously [52]. Targeting can be greatly improved bylocally controlling drug release at the site of the tumor. Thiscan be triggered through changes in the microenvironment(pH, temperature, or enzymatic) or through external stimuli(light, electric fields, magnetic fields, or ultrasound) directedat the tumor site [57–59].An alternative way to improve the uptake of NPs, bothpassive and active, has been to functionalize their surfaceswith cell-penetrating peptides (CPPs). It has been found thatcertain short ( 30-amino-acid) peptide sequences can piercecell membranes and transport drug cargo into a cell. TheseCPPs can be attached to micelles, liposomes, and other typesof NPs [60]. Certain CPPs can also act as drug carriers ontheir own, carrying small molecules and short stretches ofDNA into cells [60]. Most CPPs are amphiphilic, with a netpositive charge. Because they are shaped similar to lysingpeptides, certain CPPs can exert unwanted toxic side effects.3.3. Active Targeting. Active targeting uses ligands boundto the NP surface to improve their uptake selectivity. Theseligands can react with target cells and will often protectNPs from enzyme destruction. Ligands with a high bindingaffinity to the target cell will strongly increase deliveryefficiency. The most basic form of active targeting involvesfunctionalizing a NP with a ligand that binds to a moleculeoverexpressed on cancer cells. The issue with this, of course,is that healthy cells still express the same molecule, and ashealthy cells greatly outnumber cancer cells most of the NPsmiss their target. This issue can be mitigated by using multipleligands or by using ligands of different types.Approaches to identify potential receptors in and oncancer cells include in vivo phage screening and aptamerscreening [61]. Using in vivo phage screening, F3 was discovered to bind well with nucleolin [62], which is presentat tumor cell surfaces and in tumor endothelial cells. Thecytoplasmic proteins annexin-1 [63], plectin-1 [64], and p32protein [65] were also found through in vivo phage screening. By studying the expression of the known cell surfacereceptors in tumor vessels, other molecular markers can bedetected. For example, v𝛽3, v𝛽5 integrins, and ED-B werediscovered in angiogenic vessels using this principle [66–69]. Gene expression analysis has also been used to discoveroverexpression of collagen in tumor endothelial cells [70].A detailed review on various markers and their discoverymethods was given by Ruoslahti et al. [61].Many antibodies have been approved for use in clinicaltreatment by the FDA, such as rituximab, ipilimumab, andtrastuzumab [71]. Antibodies are among the most studiedligands because of their high specificity and availability. Anantibody conjugated dendrimer was found to bind exclusively to human prostate adenocarcinoma (LNCaP) cellsthat express PSmA (J591) [32]. Although antibodies havemany merits, they are difficult to conjugate to NPs, resultin a short circulation time, and are expensive. Peptides area promising alternative, as they are smaller, simpler, morestable, and easier to produce. Among peptides, RGD is oftenused due to its strong binding with 𝛼v𝛽3 integrin receptors.Nucleic acid base aptamers combine the advantages of bothantibodies and peptides, but they degrade quickly. Othersmall molecules can also be used as ligands, such as folic acidfor folate receptors [72]. Such molecules are small, stable, andeasy to produce. Unfortunately, ligand detection for relevantsubstrates is challenging. Even with proper binding ligandsand receptors, binding incompatibility can limit therapeuticefficiency. Multiple ligands with different charges can increaseoverall the binding affinity, but the limited binding ability andcapacity of receptors will govern the quantity and quality ofthe binding. For instance, overly strong binding can actuallyreduce tumor penetration, hinder selectivity, and lead to anoverdose of carriers [73].Active targeting alters the natural distribution patterns ofa carrier, directing it to a specific organ, cell, or organelle. Incontrast, passive targeting relies on the natural distribution ofthe drug and the EPR effect. Both of these processes dependon blood circulation and the location of initial drug delivery.However, no actively targeted NPs are commercially availablecurrently.3.4. Physical Targeting. Physical targeting navigates drugsto cancer cells using external stimulation, such as radiationor magnetic fields. For example, photothermal therapy usesNPs that once delivered efficiently convert near-infrared lightenergy to heat, killing cancer cells, and this process has fewside effects. Currently, most research is being carried outusing gold nanoparticles because they can be well controlledand have low toxicity. Their SPR (surface plasmon resonance)

Journal of Nanomaterialseffect can be tuned by shape, size, and thickness to maximizeexcitation and focus on a specific wavelength. According toa previous report, gold nanoparticles are already being testedin animals [74].Photothermal agents other than gold have also beenexplored, such as carbon nanotubes which show strongabsorbance in near-infrared region [35], and have been usedwith photothermal treatments to inhibit G2-M cell cycles[36]. Graphene is another material with potential applicationas a photothermal agent. Functionalized graphene oxide withpolymer conjugates is pH sensitive and can photothermallycause cell death [34]. In addition, silica-coated graphenenanosheets functionalized with hydrophilic polyethylene glycol have been used to deliver doxorubicin [14]. In the cases ofcarbon nanotubes and graphene oxide, pH and heat are themechanisms that initiate drug release.One limitation to photothermal therapy is that cancercells are often tolerant to environmental stress, for example,with heat shock proteins that protect the

Free drug (a) Tumor Drug-loaded NPs (b) F : Schematic contrast of drug biodistribution a er injection of free drug (a) and drug-loaded NPs (b). self-assembly), targeted drug delivery processes, and the current state of NP computational modeling. Directions for future research are also discussed. 2. Self-Assembled Nanoparticles as Delivery Vehicles

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