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Nanotechnology in Drug Delivery and TissueEngineering: From Discovery to Applications

Jinjun Shi,,

Alexander R. Votruba,

Omid C. Farokhzad,,

and Robert Langer*,,

MIT-Harvard Center for Cancer Nanotechnology Excellence and Department of Chemical Engineering,Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and Laboratory of Nanomedicine andBiomaterials, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts 02115

ABSTRACT The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilitiesin healthcare. Herein, we discuss two important aspects of nanomedicine, drug delivery and tissue engineering, highlighting theadvances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future.

KEYWORDS Nanotechnology, nanomedicine, drug delivery, tissue engineering

In pharmaceutical industries, a new molecular entity(NME) that demonstrates potent biological activity butpoor water solubility, or a very short circulating half-

life, will likely face signicant development challenges orbe deemed undevelopable. On the other hand, less activebut pharmaceutically optimal compounds may becomemore suitable candidates for development. In either case,there is always a degree of compromise, and such trade-offs may inevitably result in the production of less-idealdrugs. However, with the emerging trends and recent ad-vances in nanotechnology, it has become increasinglypossible to address some of the shortcomings associated

with potential NMEs. By using nanoscale delivery ve-hicles, the pharmacological properties (e.g., solubility andcirculating half-life) of such NMEs can be drastically im-proved, essentially leading to the discovery of optimallysafe and effective drug candidates. This is just one ex-ample that demonstrates the degree to which nanotech-nology may revolutionize the rules and possibilities of drug discovery and change the landscape of pharmaceuti-cal industries. Indeed, current nanotechnology-basedtherapeutic products have been validated through the im-provement of previously approved drugs, and many novelclasses of nanotherapeutics are now underway. 1 - 3

Drug discovery is only one of the many areas in health-care that nanotechnology is now beneting. The currentand promising applications of nanomedicine include, butare not limited to, drug delivery, in vitro diagnostics, invivo imaging, therapy techniques, biomaterials, and tissueengineering. Summarized in Table 1 are some importantopportunities that nanotechnology may afford in eachresearch area. Some of these opportunities are becomingrealities or are actually being used today, while others aregenerating promise in their early phases of development

and are expected to experience vigorous growth in theforeseeable future. As recognition of the importance of this exciting eld, it is expected that the global market of nanoscale applications in the medical eld could grow to$70 - 160 billion by 2015. 4,5 In this perspective, we dis-cuss the applications of nanomedicine with specic focuson drug delivery and tissue engineering.

Drug Delivery. Since liposomes were rst described inthe 1960s and proposed as carriers of proteins and drugsfor disease treatment, 6 nanotechnology has made a sig-nicant impact on the development of drug delivery sys-

tems. A variety of organic/inorganic nanomaterials anddevices have been used as delivery vehicles to developeffective therapeutic modalities (Figure 1). So far, thereare over two dozen nanotechnology-based therapeuticproducts approved by Food and Drug Administration(FDA) for clinical use, and more are in clinical trials. 1 - 3 Of these products, the majority are composed of a nontarget-ed delivery system (e.g., liposomes and polymers) and adrug, and are therefore considered rst generation nano-therapeutics. 7

Compared to conventional drug delivery, the rst gen-eration nanosystems provide a number of advantages. Inparticular, they can enhance the therapeutic activity by

*To whom correspondence should be addressed. E-mail: [email protected] on Web: 08/20/2010

Nanotechnology may revolutionize

the rules and possibilities of drug

discovery and change the

landscape of pharmaceutical

industries.

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prolonging drug half-life, improving solubility of hydro-

phobic drugs, reducing potential immunogenicity, and/orreleasing drugs in a sustained or stimuli-triggered fashion.Thus, the toxic side effects of drugs can be reduced, aswell as the administration frequency. In addition, nano-scale particles can passively accumulate in specic tissues(e.g., tumors) through the enhanced permeability and re-tention (EPR) effect. 8 Beyond these clinically efcaciousnanosystems, nanotechnology has been utilized to enablenew therapies and to develop next generation nanosys-tems for smart drug delivery. Below are several areas,from our perspective, that will generate medical break-throughs in the near future, and some of them could in-

spire the derivation of the next Killer Applications.New Therapeutics Delivery. Gene therapy and RNAinterference (RNAi), the two most recent and notabletherapies, hold great promise as treatment andprevention methods for various diseases. 9,10 However,the systemic administration of these new therapeutics(e.g., DNA and siRNA) is affected by several barriers suchas enzymatic degradation, uptake by reticuloendothelialsystem, kidney ltration, and limited intracellular entry.Cationic nonviral nanocarriers have, therefore, beenwidely used to encapsulate and make these newtherapeutics more efcient. Unfortunately, a substantialnumber of these materials can produce severe problems

associated with toxicity, immune or inammatory

responses, and serum instability, making them unsuitablefor clinical applications. Consequently, safe and effectivedelivery materials have become the bottleneck for thewidespread use of gene therapy and RNAi.

Recent and exciting developments are now paving theway for the clinical application of these new therapeutics.For example, high throughput screening platformtechnologies have been described and proof-of-concepthas been demonstrated by identifying cationic polymersand lipid-like-materials suitable for systemic gene andRNAi delivery. 11,12 On the other hand, rational designapproaches are also showing great potential in creatingsuccessful delivery materials (e.g., DLin-KC2-DMA 13 andcyclodextrin-containing polymer 14 ). Nevertheless, itwould also be favorable to use FDA-approved materialsfor new therapeutics delivery, as they offer specicbenets such as safety and sustained release. One suchmaterial being studied is poly(lactic-co-glycolic acid)(PLGA), a specic polymer that can be applied to formnanoparticles densely loaded with siRNA for sustainedgene silencing. 15 Beyond assuring the safety andefciency of delivery materials, more progress is neededto screen other factors, including the physicochemicalproperties of nanocarriers, targeting ligands, and

TABLE 1. Nanoscale Application in Medicine

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formulation methods, all of which can affect the deliveryof new therapeutics in vivo.

Targeted Delivery. It is widely believed that activetargeting, through the modication of nanoparticles withligands, has the potential to enhance the therapeuticefcacy and reduce the side effects relative toconventional therapeutics. 16 The ability to actively targetspecic cells rather than tissues also allows ligand-

conjugated nanocarriers to outperform rst generation,nontargeted nanosystems. While the necessity of targeteddelivery depends on various factors (e.g., deliveryvehicles, drugs, and diseases), a myriad of importantbenets have been demonstrated. 3,16 - 19

In cancer therapy, the presence of targeting ligandscan greatly enhance the retention and cellular uptake of nanoparticles via receptor-mediated endocytosis, eventhough tumor accumulation is largely determined by thephysicochemical properties of nanoparticles. 16,17 This canthen lead to higher intracellular drug concentration andincrease therapeutic activity, which is particularly

important for bioactive macromolecules (e.g., DNA andsiRNA) that require intracellular delivery for bioactivity. 16

In the case of endothelial targeting for cardiovasculardiseases or immunological tissue targeting, nanoparticlelocalization is guided by ligand - receptor interactionsrather than EPR. 18 Similarly, ligand-mediated targeting isof importance for the transcytosis of nanodrugs acrosstight epithelial and endothelial barriers (e.g., blood-brainbarrier). 19 Additionally, targeted delivery has beenapplied, in some instances, to combat multidrugresistance (MDR). 3 It is also envisioned that long-circulating targeted nanoparitcles may be able to locateand ght migrating cancer cells.

Despite three targeted nanoparticle systems now inphase I/II clinical trials, 3 the clinical translation of targeteddelivery is not as smooth as we expect. One possiblebarrier stems from the complexity behind manufacturingviable targeted nanoparticles. Targeted nanoparticlefabrication usually requires multiple steps, includingbiomaterial assembly, ligand coupling/insertion, andpurication, which could cause batch-to-batch variation

and quality concerns. The recent development of single-step synthesis of targeted nanoparticles by self-assembling prefunctionalized biomaterials provides asimple and scalable manufacturing strategy. 14,20 Anotherimportant consideration is targeting ligands. Amongothers, some variables that must be considered includeligand biocompatibility, cell specicity, binding afnity,mass production, and purity. 21 For example, to achievemaximal specicity, the ideal ligand would be able torecognize the most overexpressed receptors on targetcells relative to healthy ones. Other factors that could alsoaffect cell targeting include ligand surface density and

arrangement, as well as spacer type and length dividingligand molecules and nanoparticles. 22 Nevertheless, withadvances in ligand engineering and screening, andnanoparticle optimization, targeted delivery will become amainstay in the next generation of drug therapy.

Co-delivery. Combination therapy has shown severalpotential advantages (e.g., synergistic effects and reversalof drug resistance) and may prove more effective thansingle drug therapy. 23 However, due to the distinctpharmacokinetic proles of individual drugs, thesynergistic drug ratio optimized in vitro will undoubtedlychange after the conventional administration of drugcocktails, an outcome that could in turn lead to

FIGURE 1. Timeline of nanotechnology-based drug delivery. Here, we highlight some delivery systems that serve as important milestonesthroughout the history of drug delivery.

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maintain, or enhance tissue and organ function. 46 Overthe past few decades, continued progress in this speciceld has led to the creation of implantable tissues, someof which are already used in humans (e.g., skin and carti-lage) or have entered clinical trials (e.g., bladder andblood vessels). 47 Nevertheless, most tissue engineeringstrategies rely on the principle that under appropriatebioreactor conditions, cells seeded or recruited into three-dimensional (3D) biocompatible scaffolds are able to reas-semble into functional structures resembling native tis-sues. Early articial scaffolds were designed to providecells structural integrity on a macroscopic level, but onlyachieved moderate success. It is now widely acceptedthat to recapitulate proper tissue functionality, scaffoldsshould also establish a tissue specic microenvironmentto maintain and regulate cell behavior and function. 48

Within tissues, cells are surrounded by extracellularmatrix (ECM) which is characterized by a natural web of

hierarchically organized nanobers. 49 This integralnanoarchitecture is important because it provides cellsupport and directs cell behavior via cell-ECM interac-tions. Furthermore, ECM plays a vital role in storing, re-leasing, and activating a wide range of biological factors,along with aiding cell - cell and cell - soluble factor interac-tions. 50 Thus, the ability to engineer biomaterials thatclosely emulate the complexity and functionality of ECMis pivotal for successful regeneration of tissues. Recentadvances in nanotechnology, however, have enabled thedesign and fabrication of biomimetic microenvironmentat the nanoscale, providing an analog to native ECM. 48

Notably, these technologies have been applied to createnanotopographic surfaces and nanofeatured scaffolds,and to encapsulate and control the spatiotemporal releaseof drugs (e.g., growth factors). In turn, these nanodevicesoffer a means to direct cellular behaviors that range fromcell adhesion to gene expression.

Cell-Nanotopography Interactions. Living cells arehighly sensitive to local nanoscale topographic patternswithin ECM.49 In the pursuit to control cell function byunderlying nanotopographic cues, engineered substrateswith different nanofeatures have become rapidly adopted(Figure 2). Top-down lithographic techniques are nowutilized to create various nanopatterns, such as gratings,pillars, and pits, in a precisely controlled manner. 51

Techniques like micelle lithography, anodization, andelectrospinning can also be used to create an array of nanospheres, vertical nanotubes, and nanobers. 52 - 54

Additionally, less-ordered nanotopographies are nowbeing fabricated by polymer demixing, chemical etching,electrospinning, and phase separation processes. 55

These advances in the design of nanoscale substrateshave enabled investigators to explore cell-nanotopographyinteractions and have allowed for the manipulation of cellmorphology, signaling, orientation, adhesion, migration,proliferation, and differentiation. In particular, it has been

determined that nanogratings and aligned nanobers cangovern the alignment and elongation of many differentcell types; 54,56 - 59 the differentiation of mesenchymalstem cells can be regulated by polymer nanogratings, 58

disordered nanopits, 60 or vertically aligned TiO 2nanotubes; 53,61 endothelial cells cultured on nanogratingscan be organized into multicellular band structures,forming aligned capillary-like tubes; 56 and cell adhesionstrength and apopotosis can be controlled by thecombination of cell signaling epitopes andnanotopography. 52,62 In the near future, we can expectthe emergence of more striking results from differentcombinations of cell type, topography geometry and

scale, and substrate material. Nonetheless, the design andfabrication of next-generation nanotopographic substrateswill be guided by a greater understanding of themechanisms by which cells respond to and sensenanofeatures.

Nanofabricated Scaffolds. While critical insights into2D cell-nanotopography interactions are now enabling usto direct cell behavior, considerable efforts have beenmade to develop 3D articial scaffolds at the nanoscalefor tissue engineering applications. Nanobrous scaffoldsare now under wide investigation as they exhibit a verysimilar physical structure to protein nanobers in ECM. 48

Among the three dominant nanofabrication methods,electrospinning is a very simple and practical technique,suitable for the creation of aligned and complex 3Dstructures; self-assembly technology emulates the processof ECM assembly and can thus produce very thinnanobers; and phase separation allows for continuousber network fabrication with tunable pore structure andthe formation of sponge-like scaffolding. 63 On the otherhand, nanocomposite-based scaffolds (e.g.,nanohydroxyapatite/collagen) are very popular in hard-tissue engineering, particularly for the reconstruction of bone tissue. 64 Beyond nanobers and nanocomposites,carbon nanotubes have also attracted attention due to

FIGURE 2. Schematic of fabricated nanotopographic features usedto guide cell behaviors via cell-nanotopography interactions.

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following the very recent development of poly( -aminoesters)-DNA nanoparticles used to genetically engineeringstem cells for enhanced angiogenesis. 77

Aside from the benets discussed above,nanotechnology is also expected to play an important rolein creating novel tissue regeneration strategies (e.g., cellsheet engineering 78 ) and in surmounting other importantobstacles in tissue engineering, such as the developmentand characterization of new biomaterials and stem cellengineering. For example, high throughput assays basedon nanoliter-scale synthesis have emerged for the cell-based screening of biomaterials. 79 Despite the ongoingchallenges, we can imagine that the achievement of functional, articial tissues/organs will have extremelystrong impact on regenerative medicine, as well as othermedical elds. One exciting opportunity that lies ahead isthe idea of organ-on-a-chip 80 that, in the future, couldreplace the expensive and life-costing animal testing used

for drug development and for evaluation/optimization of nanoparticulate systems for drug delivery.

Summary. Nanotechnology is becoming the drivingforce behind a variety of evolutionary and revolutionarychanges in the medical eld. The impact of nanotechnolo-gy on drug delivery has helped to improve the efcacy of

available therapeutics and will likely enable the creationof entirely new therapeutic entities. For tissue engineer-ing, nanotechnology has also opened the door to new ap-proaches that could stimulate the reconstruction of com-plex tissue architectures. We are optimistic about thefuture of nanomedicine, given the wide array of innova-tive nanoscale materials and technologies that stand onthe horizon. With the clarication of nanotechnology-spe-cic medical regulations and a continued inux of invest-ments and time, we believe that nanomedicine will notonly improve conventional therapies, but also bridge theshortcomings of conventional medicine to help people onboth global and individual levels.

Acknowledgment. This work was supported by Na-tional Institutes of Health Grants U54-CA119349,DE013023, DE016516, EB000244, and EB006365; andthe Koch-Prostate Cancer Foundation Award in Nanother-apeutics.

NotesO.C.F. and R.L. have nancial interest in BIND Bioscienc-es and Selecta Biosciences.

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Impact of Nanotechnology on Drug Delivery Omid C. Farokhzad ,, * and Robert Langer ,, *Laboratory of NanomedicineandBiomaterialsandDepartment of Anesthesiology, BrighamandWomens Hospitaland Harvard MedicalSchool, Boston, MasMIT HarvardCenter forCancer Nanotechnology Excellence, and Department of ChemicalEngineering,MassachusettsInstitute of Technology, Cambridge, Massachuse

T he application of nanotechnologyto drug delivery is widely expectedto change the landscape of pharma-

ceutical and biotechnology industries forthe foreseeable future. 1 7 The pipelines of pharmaceutical companies are believed tobe drying up in many cases, and a numberof blockbuster drugs will come off patent in

the near-term.8

There has also been a con-current increase in the utilization of theHatch Waxman Act by generic drug com-panies, which allows them to challenge thepatents of branded drugs, further deterio-rating the potential revenues of pharma-ceutical companies. 8 The development of nanotechnology products may play an im-portant role in adding a new armamentar-ium of therapeutics to the pipelines of phar-maceutical companies. Usingnanotechnology, it may be possible to

achieve (1) improved delivery of poorlywater-soluble drugs; (2) targeted deliveryof drugs in a cell- or tissue-specic manner;(3) transcytosis of drugs across tight epithe-lial and endothelial barriers; (4) delivery of large macromolecule drugs to intracellularsites of action; (5) co-delivery of two ormore drugs or therapeutic modality forcombination therapy; (6) visualization of sites of drug delivery by combining thera-peutic agents with imaging modalities; 9

and (7) real-time read on the in vivo ef-cacy of a therapeutic agent. 3 Additionally,the manufacturing complexity of nanotech-nology therapeutics may also create a sig-nicant hurdle for generic drug companiesto develop equivalent therapeutics readily. These are just a few of the many compellingreasons that nanotechnology holds enor-mous promise for drug delivery.

Nanotechnology:BothEvolutionaryandRevolutionary. Among the rst nanotechnol-ogy drug delivery systems were lipidvesicles, which were described in the 1960sand later became known as liposomes. 10

Subsequently, a variety of other organicand inorganic biomaterials for drug deliv-ery were developed. The rst controlled-release polymer system for delivery of mac-romolecules was described in 1976. 11 Morecomplex drug delivery systems capable of responding to changes in pH to trigger drugrelease, 12 as well as the rst example of cell-

specic targeting of liposomes,13,14

wererst described in 1980. The rst long-circulating liposome was described in 1987,and the concept was later named stealthliposomes. 15 Subsequently, the use of polyethylene glycol (PEG) was shown to in-crease circulation times for liposomes 16 andpolymeric nanoparticles 17 in 1990 and1994, respectively, paving the road for thedevelopment and subsequent approval of Doxil (doxorubicin liposome) in 1995, forthe treatment of AIDS-associated Kaposis

Sarcoma. There are over two dozen nanotechnol-ogy therapeutic products that have beenapproved for clinical use to date. 18 Amongthese rst-generation products, liposomaldrugs and polymer drug conjugates aretwo dominant classes. The majority of thesetherapeutic products improve the pharma-ceutical efcacy or dosing of clinically ap-proved drugs, which in some cases also pro-vides life-cycle extension of drugs afterpatent expiration. There have been signi-cantly fewer clinical examples where nano-technology has enabled entirely new thera-peutics that would otherwise not exist; wesee this as an important area of promise fornanotechnology in the future. With nano-technology therapeutic products now vali-dated through the improvement of previ-ously approved drugs, increasing interest isexpected among academic and industry in-vestigators to revisit pharmaceutically sub-optimal but biologically active new molecu-lar entities (NMEs) that were previouslyconsidered undevelopable through con-

*Address correspondence [email protected],[email protected].

Published online January 27, 2009.10.1021/nn900002m CCC: $40.75

2009 American Chemical Society

ABSTRACT Nanotechnology is

the engineering and manufacturing

of materials at the atomic and

molecular scale. In its strictest

denition from the National

Nanotechnology Initiative,

nanotechnology refers to structuresroughly in the 1 100 nm size regime

in at least one dimension. Despite this

size restriction, nanotechnology

commonly refers to structures that

are up to several hundred nanometers

in size and that are developed by top-

down or bottom-up engineering of

individual components. Herein, we

focus on the application of

nanotechnology to drug delivery and

highlight several areas of opportunitywhere current and emerging

nanotechnologies could enable

entirely novel classes of therapeutics.

P E R S P E C T I V E

VOL. 3 NO. 1 FAROKHZAD AND LANGER www.acsnano.org16


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ventional approaches. Indeed, weexpect the emergence of nanotech-nology platforms to enable devel-opment and commercialization of entirely new classes of bioactivemacromolecules such as those in-volved in RNA interference path-ways (e.g., siRNA or microRNA) that

need precise intracellular deliveryfor bioactivity. Nearly all of the ma- jor pharmaceutical companies nowhave a RNAi franchise, and the ob-stacle to their broad clinical transla-tion is the development of robustdelivery platforms, an area wherenanotechnology can make signi-cant strides. 19

Targeting: Necessity or Luxury? Thecurrent clinically approved nano-technology products are relatively

simple and generally lack active tar-geting or triggered drug releasecomponents. Interestingly, theproducts that are currently underclinical development also lack com-plexity. In fact, nearly 29 years afterthe rst examples of targeted lipo-somes were described in theliterature, 13,14 this technology hasnot made a signicant clinical im-pact on human health; the questionis why? The answer is complex andneeds to be explored on a case-by-

case basis while considering at leastthe following points: (1) Deliveryvehicle O were the combination of biomaterials and the processes todevelop targeted drug delivery sys-tem optimal for product develop-ment? (2) Drugs O were the proper-ties of the therapeutics as well astheir site and mode of action suitedfor targeting to confer an advan-tage? (3) Diseases andindications O were the diseases forwhich targeted drug delivery sys-tems were previously explored thecorrect killer apps for targeting toconfer an advantage?

Delivery Vehicle. There are a numberof parameters that are important forthe successful development andmanufacturing of targeted drug de-livery vehicles. 20 These include (a) theuse of biocompatible materials withsimple robust processes for biomate-rial assembly, conjugation chemistry,and purication steps; (b) the abilityto optimize in parallel the myriad of biophysicochemical parameters of targeted drug delivery vehicles im-portant for pharmacokinetic proper-ties and possible cell uptake; and (c)developing scalable unit operationsamenable to manufacturing large

quantities of targeted drug deliverysystems needed for clinical transla-tion. It has been shown that the de-velopment of targeted drug deliveryvehicles by self-assembly of prefunc-tionalized biomaterials simplies theoptimization and the potentialmanufacturing of thesesystems. 20 23 The biophysico-chemical properties of the ve-hicle, such as size, charge, sur-face hydrophilicity, and the

nature and density of theligands on their surface, can allimpact the circulating half-lifeof the particles as well as theirbiodistribution. 20,21 The pres-ence of targeting ligands canincrease the interaction of thedrug delivery system with asubset of cells in the target tis-sue, which can potentially en-hance cellular uptake byreceptor-mediated endocyto-sis. More recently, surface prop-

erties of nontargeted drug deliveryvehicles such as ordered striations of functional groups 24 as well as theirshape and size 25 have also beenshown to enhance particle uptake(Figure 1).

Drugs. The choice of therapeuticfor targeted delivery needs carefulconsideration. The delivery of thera-peutics with intracellular sites of ac-tion for which cellular uptake is inef-cient may be best achieved withtargeted delivery vehicles. An ex-ample would be RNAi or antisensetherapeutics. Conversely, if a thera-peutic requires intracellular deliveryfor bioactivity, then therapeutic ef-cacy may require homogeneous tis-sue penetration and cellular uptakeof the targeted drug delivery ve-hicle, which is difcult to achieve. 26

In some cases, it is believed that tar-geting may anchor drug deliverysystems and decrease the efciencyof diffusion and uniform tissue dis-tribution. The optimization of theligand density on the drug deliverysurface can facilitate the balancebetween tissue penetration and cel-lular uptake, resulting in optimaltherapeutic efcacy. The targetingof cell surface receptors that partici-pate in membrane recycling path-ways facilitates the uptake of tar-geted drug delivery systemsthrough receptor-mediated en-docytosis. Understanding endoso-mal trafcking pathways, which arecomplex and can vary among re-ceptors, can also facilitate the engi-

Figure 1. Efcacy of nanoparticles as delivery vehicles ishighly size- and shape-dependent. The size of the nanopar-ticles affects their movement in and out of the vasculature,whereas the margination of particles to vessel wall is im-pacted by their shape.

The emergence of

nanotechnology

platforms can enable

development andcommercialization of

entirely new classes of

bioactive

macromolecules that

need precise

intracellular delivery for

bioactivity.


www.acsnano.org VOL. 3 NO. 1 1620 2009 17


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neering of suitable targeted deliv-ery systems.

Diseases and Indications. There hasbeen increasing effort to identifynew disease biomarkers and associ-ated ligands for use in targeteddrug delivery applications. Whiletargeteddrug delivery systems havebeen developed for a myriad of im-portant diseases, the thrust of re-search has been focused on solid tu-mors, cardiovascular diseases, andimmunological diseases. The cur-rently approved nanotechnologytherapeutic products for cancertherapy function by accumulatingin tumor tissue through the en-hanced permeability and retention(EPR) effect27 and releasing theirpayload in the extravascular tumortissue for antitumor efcacy. Whilethese nontargeted drug deliverysystems have been clinically efca-cious, there have been contradict-ing data regarding the added ben-et for the inclusion of targetingmolecules to these systems. 20,28 31

Tumor tissue accumulation is a pas-sive process requiring a long circu-

lating half-life to facilitate time-dependent extravasations of drugdelivery systems through the leakytumor microvasculature and accu-mulation of drugs in the tumor tis-sue. 32 This process is largely medi-ated by the biophysicochemicalproperties of the nanoparticles andnot by active targeting. 32 Therefore,even in the absence of targetingligands, drug delivery systems canbe engineered to better target aparticular tissue, or nonspecicallyabsorbed by cells, by optimizingtheir biophysicochemicalproperties. 24,25 However, once par-ticles extravasate out of the vascula-ture into the tumor tissue, their re-tention and specic uptake bycancer cells is facilitated by activetargeting and receptor-mediatedendocytosis (Figure 2). 30 This pro-cess can result in higher intracellu-lar drug concentration and in-creased cellular cytotoxicity. Whilethere is relatively modest improve-ment in tumor tissue accumulationof targeted drug delivery systemsrelative to nontargeted drug deliv-

ery systems, 29 the differ-ence in cellular cytotoxicityis more pronounced. 20,30,34

In the case of vascular en-dothelial targeting for oncol-ogy or cardiovascular indica-tions, ligand-mediatedtargeting is of critical impor-tance as tissue accumulationis not a function of EPR. 35

Similarly, in the case of im-munological tissue target-ing, such as targeted drugdelivery systems as vaccinewhere particles are trans-ported through the lym-phatic vessels to draininglymph nodes, size-mediatedtargeting has been shown tobe important for efcient

antigen presentation to cellsin the lymph nodes. 36

Nanotherapeutics are GainingTraction. With recent scienticadvances, it will be increas-ingly feasible to engineer tar-geted or multifunctionalnanotechnology products for

therapeutic applications. With thecorrect combination of an optimallyengineered vehicle, a suitable drug,and a killer app disease, the benet

of a targeted drug delivery systemover the equivalent nontargeted sys-tem is expected to be substantial. Acase in hand is the recently an-nounced completion of phase I toler-ability evaluation of CALAA-01, 37 atransferrin-targeted RNAi-nanotherapeutic for delivering siRNAto reduce the expression of the M2subunit of ribonucleotide reductase(R2) for solid tumor therapy.

In the near- and medium-term,

we can expect the emergence of many nanotechnology platforms fordrug delivery applications. Whileboth organic and inorganic tech-nologies are under development,controlled-release polymer tech-nologies and liposomes will likelycontinue to have the greatest clini-cal impact for the foreseeable fu-ture. These are exciting times fornanotechnology research, and thepace of scientic discovery in thisarea is gaining momentum. It is

Figure 2. Passive vs active targeting. (Right) Particles tend to passively extravasate through the leakyvasculature, which is characteristic of solid tumors and inamed tissue, and preferentially accumulatethrough the EPR effect. In this case, the drug may be released in the extracellular matrix and diffusethroughout the tissue for bioactivity. (Middle) Once particles have extravasated in the target tissue, the

presence of ligands on the particle surface can result in active targeting of particles to receptors that arepresent on target cell or tissue resulting in enhanced accumulation and cell uptake through receptor-mediated endocytosis. This process, referred to as active targeting, can enhance the therapeutic ef-cacy of drugs, especially those which do not readily permeate the cell membrane and require an intracel-lular site of action for bioactivity. (Left) The particles can be engineered for vascular targeting byincorporating ligands that bind to endothelial cell-surface receptors. While the presence of leaky vascula-ture is not required for vascular targeting, when present as is the case in tumors and inamed, this strat-egy may potentially work synergistically for drug delivery to target both the vascular tissue and targetcells within the diseased tissue for enhanced therapeutic.




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widely accepted that with contin-ued resources, medicine and theeld of drug delivery will be an im-portant beneciary of nanotechnol-ogy for years to come.

Conict of Interest. O.C.F. and R.L.have nancial interest in BIND Bio-sciences and Selecta Biosciences, abiopharmaceutical company devel-oping therapeutic targeted

nanoparticles.

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While both organic and

inorganic technologies

are under development,

controlled-releasepolymer technologies

and liposomes will

likely continue to have

the greatest clinical

impact for the

foreseeable future.


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