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September 24, 2013

C 2013 American Chemical Society

Facing the Truth aboutNanotechnology in Drug DeliveryKinam Park*

Departments of Biomedical Engineering and Pharmaceutics, Purdue University, West Lafayette, Indiana 47906, United States

It is debatable when nanotechnology, aswe now know it, began. Perhaps, we cantrace the beginnings to the invention of

the scanning tunneling microscope1,2 in1980, as it and the subsequently developedatomic force microscope3 enabled manip-ulation of individual atoms and molecules.The nanotechnology fever we are experien-cing now began when the United Stateslaunched the National NanotechnologyInitiative,4 the world's first program of itskind, in 2000. Since then, we have beenbombarded by the dazzling images andcartoons of nanotechnology, such as nano-robots killing cancer cells resembling theplot of Fantastic Voyage. Tens of thousandsof articles have been published on nano-technology, and the press feed the public asteady diet of potential advances due tonanotechnology.In this Perspective, the focus will be on

drug-delivery aspects of nanotechnology,specifically, targeted drug delivery to tu-mors using nanoparticles. Nanoparticles de-signed for drug delivery have been called bymany different names, including nanovehi-cles, nanocarriers, nanoconstructs, nano-spheres, etc. Here, “nanoparticle” is used torepresent all of these different formulations,including liposomes, polymermicelles, emul-sion, and solid particles made of chitosan orpoly(lactic-co-glycolic acid) (PLGA). Almostall papers on such nanoparticles end upwith the same conclusion: nanotechnologyhas great potential for drug delivery. It is true.

The question, then, is to askwhat can be doneto turn this potential into tangible outcomes,i.e., formulations that can benefit patients. Itwouldbecounterproductiveonly to talk aboutthe potential for another decade. To achievetangible outcomes, they first need to be de-fined. This, in turn, requires understanding thegoals, which may depend on individuals.

Why Do Scientists Do What They Do? Scien-tists and engineers do their work becausethey love what they do. If the goal of re-search on nanotechnology is just to makesomethingnano, new, andmorecomplicated,then the progress made in the past decadehas clearly achieved the goal, at least in part.The ultimate goal of any research in drugdelivery, however, must be to develop drug-delivery systems, nanoparticulate systems inthis case, to prevent, control, and treat debil-itatingdiseases.Most scientistsworking in thepharmaceutical andbiotechnology sectors, aswell as in academia, want to develop nano-particle formulations that can deliver drugsmore effectively to the target site for en-hanced efficacy and reduced side effects.

There are many diseases that need to beaddressed. Diabetes patients still have topoke their fingers tomeasure blood glucoselevels and to inject necessary quantities ofinsulin multiple times a day. Can this bemade easier through nanotechnology?Heart disease is the leading cause of deathin the United States. Can nanotechnologylower themortality rate? Alzheimer's diseasedevastates not only the patients themselves,

* Address correspondence tokpark@purdue.edu.

Published online10.1021/nn404501g

ABSTRACT Nanotechnology in drug delivery has been manifested into nanoparticles that can have unique properties

both in vitro and in vivo, especially in targeted drug delivery to tumors. Numerous nanoparticle formulations have been

designed and tested to great effect in small animal models, but the translation of the small animal results to clinical success

has been limited. Successful translation requires revisiting the meaning of nanotechnology in drug delivery, understanding

the limitations of nanoparticles, identifying the misconceptions pervasive in the field, and facing inconvenient truths.

Nanoparticle approaches can have real impact in improving drug delivery by focusing on the problems at hand, such as

enhancing their drug loading capacity, affinity to target cells, and spatiotemporal control of drug release.

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but also the patients' family mem-bers and friends. Can this disease beidentified early and be treated ef-fectively via nanotechnology?Manyprescription opioid drugs are widelyabused. Can nanotechnology beused to develop abuse-deterrentformulations? Cancer claims mil-lions of lives each year. Can this beprevented by nanotechnology? Un-fortunately, nanotechnology, with allof its hype and unwarranted highexpectations, has not yet producedanything significant todealwith theseissues. It is common to see studies onnanotechnology that justmake thingsmore complicated while achievingless than what traditional non-nanotechnology can do. Each inves-tigator needs to have a clear goal inwhat they are doing, rather thansimply making things more nano.

What Is Nanotechnology in Drug Deliv-ery? Of the many subareas in drugdelivery, most nanotechnology re-search has been focused on targeteddrug delivery to tumors. This specificarea will be used to define a goal andto assess the progress of nanotech-nology in the past decade.

Quite frequently, Doxil andAbraxane have been used as ex-amples of nanotechnology-baseddrug-delivery systems, mainly be-cause they are in the nanometersize range. The development ofDoxil, a PEGylated liposome formu-lation, began in the early 1980s andwas approved by the US Food andDrug Administration (FDA) in 1995.5

The main reason for approval wasthe equivalent efficacy and reducedcardiotoxicity or improved safetyprofiles as compared with freedoxorubicin.5 The promise of nano-technology in drug delivery is todeliver a drug selectively to thetarget site for enhanced efficacywith reduced side effects. In thatsense, a portion of the nanotechnol-ogy promises were achieved. Lipo-somes have been known for 60years,6 and PEGylation has beenknown for 40 years.7 Abraxane is asimple formulation based on oil/water (o/w) emulsion.8 Paclitaxel-dissolved methylene chloride is

emulsified in albumin-dissolvedaqueous solution to form an o/wemulsion, and subsequently homo-genized to form nanodroplets.Albumin-coated paclitaxel nanopar-ticles are obtained by evaporatingthe solvent under reduced pressure.Albumin-coated nanocrystals canalso be formed by simply addingalbumin (as a surface modifier) tocoarse drug crystals during milling9

or to the formed nanocrystals. Thesize of Doxil and Abraxane is cer-tainly at the nanoscale, but neitherof these formulations was inspiredby modern nanotechnology. Theywere prepared bymethods that werealready widely practiced before theconcept of modern nanotechnologyevolved. Does any drug-delivery for-mulation become a nanotechnologysystem just because the size is at thenanoscale, regardless of how it ismade? If that is the case, the currentnanotechnology in drug-delivery sys-tems is just a name change withoutany technological advances.

Understanding the Limitations of Nano-technology. New generations of scien-tists need to focus on solving theproblems that are indeed worthwhile.Tom Friedman, in his book That UsedTo BeUs,10 states, “One thingwe knowfor sure: The path to a happy endingbegins with the awareness that some-thing is wrong, that changes are ne-cessary, and that we the people haveto be the agents of those changes” (p348). One problem now is how nano-technology is perceived.11 The nextgenerations of scientists will have tobe the agents of these changes.

One of the changes to be madeis to stop spreading inaccurate in-formation. Findings made in thisarea, which may be true only underlimited experimental conditions,are frequently inflated and over-blown with the futuristic rhetoricby the press and the media. Suchrhetoric may be necessary to attractthe public's attention to nanotech-nology and, thus, more funding,but these statements create un-intended side effects. Researchersmay be forced to create fiction-likestories for funding, instead of

proposing solutions to real pro-blems. Many reviewers at fundingagencies, without a clear under-standing of the field, may demandsomething innovative over theexisting technology. It will be extre-mely difficult, for example, to pro-pose something better thanmakingnanoparticles that “selectively lockonto only the cancer cells”.

History of Drug-Delivery Technologies.A brief overview of the history oncontrolled drug delivery providessome insight into how the cur-rent nanotechnology-based drug-delivery systems have evolved. Asshown in Figure 1, the drug-deliverydiscipline is 60 years old. The firstgeneration (1G) of drug-deliverysystems was developed from theearly 1950s to the end of the1970s. During this time, the basicmechanisms of controlled drug re-lease were established. Most of thedrug-delivery formulations were fororal and transdermal administration,and thus, the duration of drug re-lease ranged from 12-h (twice-a-day) oral formulations to 1-weektransdermal formulations. Sincethen, numerous clinical productsfor oral delivery have been intro-duced to the market. The secondgeneration (2G) from 1980 to 2010

Does any drug-delivery

formulation become a

nanotechnology system

just because the size is

at the nanoscale,

regardless of how it is

made? If that is the

case, the current

nanotechnology in

drug-delivery systems is

just a name change

without any

technological advances.

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was not as successful at introducinguseful clinical systems. Extensive ef-forts were made to develop zero-order release techniques, whichturned out not to be necessary. Adozen extended release depot for-mulations were developed, but thiswasminor compared with the thou-sands of oral controlled-release for-mulations available to patients.Other efforts on modulated (i.e.,self-regulated) drug-delivery sys-tems, e.g., glucose-dependent insu-lin delivery systems, have not beenfruitful. This is mainly due to thedifficulties associated with makingan implantable closed system thathas both glucose sensing and insu-lin release controlling abilities. Atthe turn of the 21st century, theNational Nanotechnology Initiativeinitiated the current nanotechnol-ogy fever. During the fever, “newand innovative” often meant “nanoand complicated”. The assumptionwas that the nanosized materialswould have properties differentand unachievable by microsizedand larger materials. The assump-tion was thought to be reasonable,and thus, making something nanowas all that was required at thattime.

Convenient Misconceptions. In thearea of targeted drug delivery, nano-technology fever was fueled byan observation of the behavior ofnanoparticles in tumors in mice,known as the enhanced permeationand retention (EPR) effect.13 TheEPR effect is considered to be re-sponsible for increased delivery ofnanoparticles to targeted tumors inmouse experiments. This notionevolved into an idea that onlynanoparticles have the EPR effect.Careful analysis of the originaldata, however, indicates that albu-min and IgG are actually better inaccumulating at the tumor site.14 Itis also thought that PEGylated nano-particles increase their blood circu-lation times, which in turn may en-hance the EPR effect.15 Thus, it hasbeen widely assumed that PEG-ylated nanoparticles having theEPR effect will result in an enhancedtumor-killing effect, and therefore, theproblem of targeted drug delivery totumorswaspartially solved. The realityis that these assumptions have pro-duced numerous research articles buthave made no significant advances intranslation into patient treatment.16

These convenient misconceptionshave to face the inconvenient truth.

Inconvenient Truth. Nanoparticleformulations, as compared with solu-tion formulations, increase the drugconcentration around a tumor by100�400% (Figure 2 circle). Theseincreases are phenomenal by anymeasure. What is missing here,however, is the big picture showingthe full story on drug delivery. Itshould be understood that >95%of the administered nanoparticlesend up at sites other than the tar-geted tumor (Figure 2); this fact hasbeen largely overlooked.11 Clinicalapplications of Taxol, Taxotere,Abraxane, and Genexol show thatthe latter two nanoparticle formula-tions have similar performance tothe first two, which is based onsolution formulations. The amountof a drug delivered to the targettumor may be about the same fordifferent formulations. Taxol, Abrax-ane, and Genexol deliver paclitaxel,while Taxotere delivers docetaxel, aderivative of paclitaxel. Nanoparti-cles may provide an alternative wayof making aqueous solution formu-lations for intravenous administra-tion of poorly soluble drugs with-out using undesirable excipients,such as polysorbate 80 or cremo-phor EL.17 This is a great use of

Figure 1. Evolution of controlled drug-delivery systems. Adapted with permission from ref 12. Copyright 2013 Springer.

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nanoparticle approaches. It is sim-ply different than the widely be-lieved notion that nanoparticleswould be far superior to nonparti-culate solution formulations.

OUTLOOK AND FUTURE CHAL-LENGESTurning the potential of nanopar-

ticle systems into clinically usefulformulations requires setting upclear, realistic goals. The challengesin targeteddrugdeliveryusingnano-particles can be overcome throughunderstanding the limitations ofnanoparticle approaches and max-imizing the existing capabilities ofnanoparticle formulations.

Exploit the 5% Reaching the TargetTumor. Nanoparticles go to targettumors simply as a result of bloodcirculation. Thus, the percentage ofthe administered drug reaching thetumor is similar regardless of theformulation type. The nanoparticlesremain around the tumor longer,because they do not diffuse backinto the bloodstream as easily asdissolved drug molecules. This re-sults in more accumulation of thedrug near the tumor site. Assuming5% of the total administered nano-particles can end up at the tumorsite, one can make a nanoparticlesystem a clinically useful formula-tion. Currently, the drug loading in

most nanoparticles is not high,usually around 10%. If the drugloading can be increased by a factorof 5, it is the equivalent of delivering25% of the total administered nano-particles with 10% drug loading.For example, instead of loading adrug into liposomes or polymer mi-celles, one can use the drug nano-crystals themselves, which deliver100% of the drug.18 The surface ofthe nanocrystals may need to bemodified by polymers or proteinsfor enhancement of their affinity tocells or their stability.19 The percen-tage of the drug may decrease, butthe majority of the total weightwill be the drug. This approach, ofcourse, deliversmore drugs to othertissues, too, and this is where thereduced toxicity by nanoparticle ap-proach is important. It is necessaryto develop nanoparticle formulationshaving significantly reduced side ef-fects by controlling the drug releasedepending on the environment. Thedrug delivery field can be advancedrapidly by making nanoparticles withhigh drug-loading capacity and theability to control the drug release.

Once the tumor site is reached,nanoparticles need to be clearedfrom the site after releasing theloaded drug. If the empty nanopar-ticles remain at the same site due tothe low clearance rate, they may

present a physical barrier for deliv-ery of additional nanoparticles thatare freshly administered. Extrava-sated liposomes 90 nm in diameterwere observed to remain near theblood vessels even after 1 week.20

The study of in vivo degradation ofnanoparticles, made of PLGA (L:G =50:50, Mw = 44 000 Da) sized 200and 500 nm, indicates that morethan 1/3 of the administered nano-particles remain not degraded after1 week.21 Thus, nanoparticles needto be designed to undergo timelyclearance from or degradation atthe target site. Currently, little atten-tion has been paid to this property.

Entering the Tumor Cells. For a drugto be effective, it needs to enter thetumor cells. Thus, improving the cel-lular interaction, leading to cellularuptake, is another necessary inno-vation. In an attempt to maximizeinteractions with the cell, a newnanocage approach was devel-oped. In this issue of ACS Nano,Professor In-San Kim and his groupdescribe a nanocage they designedthat displays a high affinity to cellreceptors.22 Specific peptides iden-tified by phage display were geneti-cally fused onto the surface ofcage proteins. Symmetrical assem-bly of the cage proteins forms clus-ters of the peptides in bunches.The resulting peptide bunches on

Figure 2. Relative distribution of a drug at a target tumor site by (A) conventionalsolution formulation and (B) nanoparticulate formulation. The majority of theadministered drug ends up at nontarget sites, but the 5�more efficient delivery ofthe drug by nanoparticles can be exploited for maximizing drug efficacy. Adaptedwith permission from ref 12. Copyright 2013 Springer.

The challenges in

targeted drug delivery

using nanoparticles can

be overcome through

understanding the

limitations of

nanoparticle

approaches and

maximizing the existing

capabilities of

nanoparticle

formulations.

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the nanocage synergistically in-crease the affinity of the peptideligands, leading to substantial in-creases in therapeutic efficacy. Ifsuch a nanocage can be grafted tothe surface of drug nanocrystals, thetherapeutic effect will be enhancedconsiderably.

The high affinity of nanoparticlesto the cell surface may have theadded benefit of increasing the in-tratumoral distribution of the nano-particles. Extravascular transport,and thus the tumor-targeting effi-ciency of nanoparticles, dependson the nature of targeting ligandsattached to the nanoparticle sur-face.23 Receptor-mediated transcy-tosis can facilitate extravasculartransport of nanoparticles, leadingto enhanced nanoparticle deliveryto solid tumors. It overcomes thebarrier to efficient dispersionof nano-particles in tumor interstitium. Theefficient delivery of nanoparticlesinto the tumor interstitum exposestumor cells to lethal doses andmakes them less susceptible to thedevelopment of resistance. The pre-sence of agonists on the nanoparti-cle surface may not improve thedelivery from blood circulation tothe target site, but can enhance sub-sequent extravascular transport.24

Dealing with Biological Issues. Evenif nanoparticles are designed tohave high affinity to the tumor cellsurface, the actual interaction be-tween the two occurs when thetumor cells express the receptors.It needs to be understood that notall tumor cells express receptors.More importantly, tumor cells maynot have overexpressed receptorsat the time of nanoparticle arrival.The heterogeneity in tumor cellsthemselves and temporal receptoroverexpression are not an easilyaddressed problem.25 Thus, nano-particles with the ability to controldrug release depending on environ-mental conditions become evenmore important.

Time To Be Realistic. A few clinicalstudies were done to test the newlydeveloped nanoparticle formula-tions. For example, a thermo-sensitive

liposome formulation, which showedexcellent efficacy inmousemodels,26,27

was tested for its efficacy in clinicalstudies. Patients were treated withheat before administration of thelow temperature-sensitive liposomeformulation. The result was not asgood as expected and did not meetthe goal of demonstrating evidenceof clinical effectiveness.28 For thisapproach to be successful, it mayrequire fine-tuning of the proce-dure to maximize the usefulness ofthe liposome properties. Appar-ently, the optimal condition foundin small animal studies was notoptimal in a clinical application.The differences in size and othervariables between small animalsand humans may require changesin the time and duration of heatexposure. Enormous resources re-quired for clinical studies, however,prevent repeated clinical experi-ments. This necessitates devel-opment of improved animal andin vitro models that can providebetter predictions on nanoparticleefficacy in humans. It is difficult, aswell as unnecessary, to develop asingle model that represents all as-pects of human physiology. It willbemore than sufficient if eachmod-el can predict one or more aspectsof nanoparticle behavior in humans.Microfluidic devices can test theeffectiveness of nanoparticles to ex-travasate from the blood vessel intothe surrounding tissues and sub-sequent clearance from the site.29,30

A three-dimensional tumor spher-oid model can be used to exam-ine how effectively nanoparticlesinteract with the cells on the sur-face and achieve intratumoraldistribution.31

One thing that nanoparticle sci-entists need to realize is that clin-ical application of any formulationrequires approval by the FDA or itsequivalent overseas. The safety andefficacy of new formulations mustbe proven through controlled clin-ical studies. Pharmaceutical andbiotechnology companies preferusing excipients that have alreadybeen used in clinical products

approved by the FDA. In this way,therewill be little concern about thesafety and toxicity of the excipientsthemselves. This brings another con-straint in developing clinically usefulnanoparticle formulations. By under-standing the many limitations andconstraints in developing clinicallyuseful formulations, nanoparticlescientists can have a better perspec-tive in their pursuit offinding thenextgenerations of drug-delivery systems.Achieving “the next big thing” startswith being realistic now. There simplyneeds to be an understanding thatovercoming theenormousdifficultiesinvolved in clinical applications ofnanoparticles requiresmore than justrhetoric and pretty pictures.32

Conflict of Interest: The author de-clares no competing financial interest.

Acknowledgment. This work was sup-ported by National Institute of Healththrough CA129287 and GM095879, andthe Showalter Research Trust Fund.

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In this issue of ACS

Nano, Professor In-San

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to cell receptors.

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