theranostics: are we there yet?

Theranostics: Are We There Yet?Sonke Svenson*

Drug Delivery Solutions LLC, 16 Temple Street, Arlington, Massachusetts 02476, United States

ABSTRACT: The U.S. National Institutes of Health throughthe National Cancer Institute (NCI) have been charged withthe goal of eliminating death and suffering from cancer by theyear 2015. In order to achieve this very ambitious goal, thedevelopment of novel nanotechnology-based devices andtherapeutics that are capable of one or more clinicallyimportant functions is envisioned. There is great hope andexpectation in the development of theranostic nanocarriers,which combine diagnostic and therapeutic agents in one entity.Main delivery approaches include prodrugs, liposomes,polymersomes, and polymeric micelles and nanoparticles.Diagnostic and therapeutic agents are physically entrapped orconjugated to the nanocarriers, or they are conjugated tocarefully designed polymers which subsequently form nanocarriers. This focus discusses pros and cons of the different theranosticapproaches and tries to answer the question which approach has the highest probability to translate into the clinic and benefitpatients. Carefully designed polymers, conjugated with diagnostic and therapeutic agents, that either self-assemble or can beprocessed to form nanocarriers offer clear advantages over random physical entrapment or conjugation of these agents to existingnanocarriers. These polymers can optionally be fitted with terminal stabilizing or anchoring functionalities and a targeting ligand.However, the need for nanocarriers that are subjected to the enhanced permeability and retention (EPR) effect to carry ligandsfor active targeting still needs to be demonstrated. Thirty-seven of the 41 nanocarrier-based formulations that are on the marketor are under investigation at different levels of clinical development rely on passive targeting. The answer to the title question,not surprisingly, can only be no, but very promising approaches are being developed that have the potential to translate into theclinic and meet regulatory requirements.

KEYWORDS: theranostic nanocarriers, liposomes, polymersomes, polymeric micelles, polymeric nanoparticles,diagnostic and therapeutic agents, functionalized polymers, nanomedicine

1. INTRODUCTION

The U.S. National Institutes of Health through the NationalCancer Institute (NCI) have been charged with the goal ofeliminating death and suffering from cancer by the year 2015.In order to achieve this very ambitious goal, the development ofnovel nanotechnology-based devices and therapeutics that arecapable of one or more clinically important functions, includingdetecting cancer at its earliest stages, pinpointing its locationwithin the body, delivering anticancer drugs specifically tomalignant cells, and determining if these drugs are killingmalignant cells, is envisioned. The NCI Alliance for Nano-technology in Cancer was approved in July 2004 and providedwith US$145 million for phase I (2005−2010). The allianceidentified six major challenge areas, including “MultifunctionalTherapeutics”, i.e., nanoscale devices that integrate diagnosticand therapeutic functions, targeting properties, and control ofthe spatial and temporal release of therapeutic agents whilemonitoring the effectiveness of these agents.1 The scientificstrategy for phase II (2010−2015) of the program wasformulated based on the lessons learned from phase I, theevolving strategy of the National Nanotechnology Initiative(NNI), and the input of the extramural community. Phase II ofthe program, funded with approximately US$30 million per

year, promotes early diagnosis and improved monitoring oftherapeutic efficacy.2 This combination of therapy anddiagnostics in a single treatment is often referred to as“multifunctional” or, increasingly, as “theranostic”, a termoriginally used to describe the two-step process of diagnostictherapy for individual patients, namely, first, to test patients forpossible reaction to a new medication and, second, to tailortheir personalized treatment based on these test results.3 At thisstill early stage of development of the field both terms,multifunctional and theranostic (sometimes also calledtheragnostic) are often used interchangeably with no cleardefinition of potential differences. One should also note thatmultifunctional and theranostic nanocarriers often contain atargeting ligand as a third component of the particlecomposition.

Special Issue: Theranostic Nanomedicine with Functional Nano-architecture

Received: November 9, 2012Revised: January 18, 2013Accepted: January 22, 2013Published: February 4, 2013

Review

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Given this challenge to develop theranostic or multifunc-tional treatmentsand the accompanying funding opportu-nities from the NCI Allianceit is not surprising that theapplication of nanocarriers for combined targeting and deliveryof diagnostic and therapeutic agents has received increasingattention in recent years. A brief review of publications resultingfrom a SciFinder search of theranostic or multifunctionalnanocarriers in medical applications (mostly oncology)between the years 2000 and 2011 gave increases from zero toabout 120 (theranostic) and 160 (multifunctional) annualpublications, respectively, with around 150 articles each onthese two topics published in 2012 alone (Figure 1). Other

indicators of the increasing importance of theranostics are theintroduction of Theranostics at the beginning of 2011, an openaccess journal published by Ivyspring International Publisherand edited by Xiaoyuan (Shawn) Chen from NIH’s NIBIB, andthe publication of special theme issues by journals such asAccounts of Chemical Research (2011), Molecular Pharmaceutics(2010), and Advanced Drug Delivery Reviews (2010), as well asthe present theme issue by Molecular Pharmaceutics.

2. THERANOSTIC NANOCARRIERSOPPORTUNITIESAND CHALLENGES

Nanocarriers may be constructed from a wide range of organicand inorganic materials such as polymeric nanoparticles,emulsions, nanocapsules, nanospheres, micelles, liposomes,dendrimers, quantum dots (QD), and fullerenes and carbonnanotubes (CNT). These materials are being used toencapsulate or solubilize chemotherapeutic agents for improveddrug delivery in vivo or to provide unique optical, magnetic, andelectrical properties for imaging. The next generation ofnanocarrier-based research is directed at the consolidation offunctions into multifunctional devices, ultimately facilitating therealization of personalized therapy. These multiplexed nano-carriers are capable of (1) improving the delivery of poorlywater-soluble drugs; (2) identifying malignant cells viamolecular detection; (3) visualizing their location in the bodyby providing enhanced contrast in medical imaging techniques;(4) fostering transcytosis of drugs across tight epithelial andendothelial barriers; (5) targeting and killing diseased cells withminimal side effects through selective cell or tissue targeting;(6) temporal control of drug release; (7) monitoring treatmentin real time; and (8) codelivery of multiple drugs for

combination therapy.4−8 Nanocarriers are an ideal platformfor theranostics because particles with sizes below 100 nm areable to take full advantage of the irregularly dilated and leakytumor blood vessels with pore sizes in excess of 100 nm andextravasate into tumor tissues. Together with the reducedlymphatic drainage of tumor tissues, this enhanced permeabilityand retention (EPR) effect leads to tumor accumulation ofnanocarriers. At the same time, nanocarriers larger than 10 nmin size can avoid first pass renal clearance (threshold of 8−10nm), leading to extended circulation times, and also avoidextravasation from intact blood vessels (pore size <10 nm) intohealthy tissues, reducing the risk of undesired side effectsduring treatment. Based on the composition of diagnosticagents, theranostics are often divided into groups such as gold-based, magnetic (mostly iron oxide-based), polymeric, silica-based, carbon, and composite nanomaterials.9−15 However,retrofitting existing diagnostic agents with a therapeutic activecarries little weight for the development of novel theranosticagents because the main problems with small moleculetreatment remain unchanged: rapid renal clearance and largevolume of distribution (Vd), requiring the application of highdoses to ensure that the therapeutic concentration at the targetsite can be achieved. High doses of actives are arguably themain reason for undesired, often debilitating side effects ofconventional therapy, and adding a potentially cytotoxicdiagnostic agent to a cytotoxic drug is not helpful. In addition,while gold or iron oxide nanoparticles, for example, areexcellent diagnostic tools for imaging applications, they providelimited cargo space for therapeutic payloads within theirprotective coatings, applied to prevent particle aggregation andrecognition by the mononuclear phagocyte system (MPS).These retrofitting approaches will therefore not be discussedhere; the focus of this discussion will be based on “classic”nanocarriers such as liposomes, polymersomes, and polymericmicelles and nanoparticles. These nanocarriers can be loadedwith sufficient quantities of diagnostic and therapeutic agentsand, therefore, provide ample opportunity to developtheranostic agents with promise to translate into the clinicand benefit patients. Nanocarriers offer complementary sizeranges and volumes for medical applications, with liposomes(80−200+ nm) being the largest particles, followed bypolymeric nanoparticles (40−100 nm), polymeric micelles(20−60 nm), and dendrimers (<10 nm). The small size andlimited cargo space of dendrimers, another proposed nano-carrier for theranostic applications, qualifies them mainly fordiagnostic and imaging applications where fast renal clearance isdesirable. Most theranostic nanocarriers are built upon fourbasic components: signal emitter, therapeutic payload, payloadcarrier, and targeting ligand.16

The increasing research activities and attention totheranostics over the past few years and the fast approach ofthe target year 2015 beg the question “Are we there yet?” Mosteditorials, perspectives, and reviews collected in theme issueswould provide a very positive outlook and response to thisquestion. However, in order to keep the focus not only on theachievements in the field but also on the still remainingchallenges that need to be addressed, critical considerationsshould not be avoided. One major concern with theranostictherapies arises from the opposing timelines and concentrationsof diagnostics (and imaging for that matter) and therapy. Themain goal in diagnostics and imaging is to provide as little agentas necessary for as short a time as possible to achieve a strongsignal-to-background ratio. Low amounts of imaging agents and

Figure 1. Number of annual publications of theranostic (dark bars)and multifunctional (light bars) nanocarriers in medical applicationsfor the years 2000 to 2012 (October). Arrows indicate the beginningof phases I and II of the NCI Alliance for Nanotechnology in Cancer.

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rapid (renal) clearance from the body are desired to reduce therisk of adverse effects. On the contrary, therapy requires theapplication of as much active as possible (“maximum tolerateddose”, MTD) for as long as possible for the highest achievabletherapeutic index. How can these opposing requirements bealigned in a theranostic therapy, and are they even discussed inreviews and research articles on the topic? Three potentialapproaches to address this dilemma come to mind, the firstapproach maintaining the original two-step process oftheranostics in which preferably identical nanocarriers are firstloaded with a diagnostic agent to identify the personalizedaccumulation, retention, and excretion of these carriers in apatient, followed by the same nanocarrier loaded with atherapeutic active. If the presence of diagnostic and therapeuticagents does not affect size, shape, and surface composition ofthe nanocarrier, then there is a good chance thatpharmacokinetics (PK) and biodistribution are largely un-affected. One example for converting a purely imagingnanocarrier into a theranostic agent is by simply switching aradionuclide associated with the carrier from a γ-emitter (111-In) to a β-emitter (90-Y), provided that the nanocarrier hassuitable chelators for such radiometals.3 This approach wouldaddress the opposing concentration needs of diagnosis andtherapy but not the opposing residence times because theidentical nanocarriers would clear from the body following thesame timeline. The second approach would involve theranosticcarriers in which the active can serve as diagnostic agent and,after application of an external trigger, as therapeutic agent aswell. Gold and iron oxide nanoparticles for imaging andphotothermal and hyperthermal therapies after irradiation aretwo examples of this approach.17 In this scenario concentrationneeds and residence times would be the same; however, notmany actives can serve as diagnostic and therapeutic agent,limiting the options for diagnosis and therapy. The thirdapproach would involve the therapeutic nanomedicines whichare currently being developed but combining them with abiocompatible diagnostic agent that could remain in the bodyfor extended times and would not cause unacceptable harm ifreleased from the nanocarrier, for example during itsdegradation: a common way to release encapsulated drugsinside tumor tissue. Gold and some metal oxides might meetthis requirement. For magnetic resonance imaging (MRI) onecould imagine encapsulating the same gadolinium(III) chelatesthat are currently approved (e.g., Magnevist, OMNISCAN, orProhance) into a therapeutic nanocarrier. The release of theseGd(III) complexes during treatment would then expose anagent to the body that has regulatory approval. However, thisapproach has the setback that the concentration of releasedGd(III) complex would need to be tightly controlled becausethere is evidence that Gd(III)-based agents may be associatedwith a toxic reaction known as nephrogenic systemic fibrosis(NSF) in patients with severe kidney problems. Release ofGd(III) ions from the complex is suspected to be responsiblefor this toxicity. This hypothesis is supported by experimentsshowing that, despite a 50-fold range of LD50 values for fourGd(III) complexes, all became lethally toxic when precisely thesame quantity of Gd(III) ions was released.18,19 A third,recently published example involves porphyrin-based photo-sensitizers, which are useful agents for photodynamic therapy(PDT) and fluorescence imaging of cancer. Porphyrins are alsoexcellent metal chelators, forming highly stable metallocom-plexes for the delivery of radioisotopes. This approach has beendemonstrated by chelation of 64-Cu into a porphyrin-peptide-

folate probe (PPF), turning the 64-Cu−PPF complex into apositron emission tomography (PET) theranostic probe.20 Thestable 64-Cu−porphyrin complex is expected to notprematurely release 64-Cu or negatively affect the eliminationof the porphyrin probe.Besides opposing concentration and residence time needs,

another very important challenge of nanocarrier-basedtheranostics that needs to be addressed is the polydispersitywithin a particle population. Even when the nanocarrier itselfcan be made fairly monodisperse in size, loading of the carrierwith a diagnostic agent by random physical entrapmentgenerally leads to broad distribution. This situation is similarfor entrapment of the therapeutic agent and, of course,multiplied if both agents are entrapped within the samepopulation of nanocarriers. The situation becomes even morecomplex when targeting ligands are randomly added to thesenanocarriers in an attempt to enhance the selectivity of particleuptake at the target site. For example, DOXIL has become thearguably most successful nanomedicine because of itssimplicity. Although it is safe to assume that not all liposomeswithin a batch carry the same amount of doxorubicin but thatthere is a drug distribution, all liposomes are PEGylated andtheir tumor cell uptake via the EPR effect will be equally likelyas long as their size distribution is narrow. Therefore, it is alsosafe to assume that the average drug concentration measured inbulk will correlate with the drug concentration inside tumortissues. The moment an active targeting ligand is randomlyadded to these liposomes, their surface composition andtherefore circulation time, biodistribution, and tumor celluptake will vary dependent on the number and density oftargeting ligands, and the correlation between bulk drugconcentration and actual drug concentration inside tumorcells will be lost. Loading nanocarriers by chemical conjugationof diagnostic, therapeutic, and targeting moieties to apreformed nanocarrier instead of physical entrapment doesnot reduce polydispersity, unless there are driving forcesengineered into the particle that allow selective conjugation.Polydispersity within a nanocarrier population will raiseregulatory concerns and, therefore, delay if not preventtranslation into the clinic.Unfortunately, analytic characterization of the bulk nano-

carrier population with standard methods will not reveal thispolydispersity. For example, conjugating the targeting ligandfolic acid (FA) and the anticancer drug methotrexate (MTX) tothe surface of a poly(amidoamine) (PAMAM) dendrimer ofgeneration 5 (G5) gave a bulk composition of four FA and fiveMTX per dendrimer. Careful separation and analysis of theresulting fractions revealed, however, that only 4% of thepopulation had this composition, while the remaining 96% werecomposed of a mixture of combinations of the conjugatedagents.21 This complex situation not only has potentialregulatory consequences if regulatory agencies do not acceptbulk analysis but require a more detailed analytic character-ization of a theranostic formulation, but it also can havebiological consequences. Different amounts of targeting ligands,for example, can lead to different biodistribution, nanocarrieruptake profiles, and residence times because it is well-knownthat multivalent interactions between cell receptors andnanocarrier ligands at high ligand surface density aresubstantially stronger than single or isolated receptor−ligandinteractions.22 Schematic presentations of complex nanocarriersoften suggest the potential of these structures as nanomedicinesbut do not easily reveal the accompanying challenges (Figure



2A). However, there are few examples addressing thepolydispersity challenge. Coincidently, another dendrimer has

been carefully designed to carry three different surface groupsfor controlled conjugation, namely, nine azide, nine amine, andfifty-four terminal acid groups (Figure 2B). This nanocarrierwould allow selective further modification of these surfacegroups with targeting ligands, imaging agents, or therapeuticagents, leaving the free acid groups to provide water solubilityor to add groups shielding the active agents, for examplepoly(ethylene glycol) (PEG) chains.23 In this review, differentapproaches to theranostic nanocarriers that have come to theforefront of this important research area over the last years willbe discussed with the main emphasis on the polydispersitychallenge and minor emphasis, as data is available, on high vslow dose and long vs short residence time in order to find ananswer to the title question. Most research is published incancer treatment, and therefore, most examples presented herewill address cancer therapy. However, theranostics are alsoapplied in inflammation (inflamed tissue is also prone to theEPR effect), cardiovascular disease, atherosclerosis, anddegenerative diseases such as Alzheimer’s disease.24−26

3. THERANOSTIC PLATFORMS3.1. Prodrugs. The simplest approach to a functional

therapeutic agent is formed by a prodrug in which a targetingligand is conjugated to a therapeutic active which either hasinherent imaging activity or can be fitted with an imaging agentas described earlier for the (64-Cu-porphyrin)-peptide-folateprobe.20 Similarly, the topoisomerase I inhibitor camptothecin(CPT) as the drug was conjugated via a cleavable disulfide

bond to a naphthalimide moiety as a fluorescence reporter thatgives rise to a strong, red-shifted fluorescence signal uponcleavage of the disulfide bond, and a cyclic peptide containingthe RGD (Arg-Gly-Asp) sequence to target the αvβ3 integrinreceptor. The cRGD sequence targets tumor cells, andglutathione (GSH) and thioredoxin (Trx) inside these cellsrelease CPT as monitored by the fluorescence shift.27 An evensimpler construct is the prodrug formed between doxorubicin(DOX) and the folate ligand via a disulfide bond. The DOX−folate conjugate quenches the inherent fluorescence of DOX;however, the fluorescence becomes activated after intratumoraldisulfide cleavage by GSH. Both building blocks of thisprodrug, DOX and folic acid, are approved in cancer therapy.28

Protease-activated prodrugs (PAPs) represent another ap-proach to combat diseases such as cancers, atherosclerosis,and Alzheimer’s disease.26 Proteases play a fundamental role inmany biological and pathological processes through selectivecleavage of specific substrates (proteolysis). Overexpression ofcertain proteases in diseased cells can therefore be utilized torelease drugs from prodrugs similar to the application of GSH-activated prodrugs. Another example of this approach, usingspecific substrates to release drugs in a controlled manner, isbased on Sn-2 lipase-labile phospholipid prodrugs, asdemonstrated using the potent antiangiogenic mycotoxinfumagillin.29 Polydispersity associated with nanoparticles isnot an issue with these prodrugs, and the competingconcentrations of diagnostic and therapeutic agents could beaddressed, for example, by loading the diagnostic agent onlyinto a fraction of the prodrugs or by using building blocks thatdo not trigger adverse effects after prodrug dissociation.However, first-pass renal clearance would be a concern giventhe usually small size of these prodrug complexes.

3.2. Liposomes and Polymersomes. Liposomes have along and successful clinical history as nanocarriers for thedelivery of therapeutic agents, for example doxorubicin(DOXIL). With a size range of 80−200+ nm, they provideplenty of cargo space within their aqueous core for hydrophilicguest molecules as well as space within the bilayer lipidmembrane for hydrophobic species. The surface of liposomescan be functionalized with poly(ethylene glycol) (PEG) chainsto provide “stealth” properties against the mononuclearphagocyte system (MPS) or with targeting ligands to provideactive targeting properties. For imaging purposes, i.e., formagnetic resonance imaging (MRI), superparamagnetic ironoxide (SPIO) can either be coated with a lipid layer (smallmagnetoliposomes, MLs) or several SPIOs or gadolinium(III)chelates can be entrapped into the aqueous core of liposomes(large MLs). These large MLs provide additional cargo spacefor drug encapsulation, into either the core or the lipidmembrane, rendering MLs theranostic agents.30,31 An alternat-ing magnetic field can be utilized to heat SPIOs forhyperthermia treatment or to release encapsulated drugs intotumor tissues. In order to improve loading of MLs with SPIOs,a new method has been developed allowing encapsulation ofSPIOs up to a volume fraction of 30% (ultramagneticliposomes, UMLs).32 Targeting of MLs can be achieved byusing a static magnetic field in the vicinity of tumors.Alternatively, folate-PEG-(cholesteryl hemisuccinate) can beadded to the outer layer of liposomes for active targeting to thefolate receptor on tumor cells.33 Multimodal imaging propertieshave been achieved by encapsulation of fluorescence dyes suchas calcein, or by entrapment of quantum dots (Qdots) into thelipid membrane of liposomes. Therapeutic agents such as

Figure 2. (A) Theranostic nanoparticle, randomly carrying targetingligands, imaging agents, and therapeutic agents in the core and on thesurface. Reproduced with permission from ref 14. Copyright 2011American Chemical Society. (B) Dendrimer, designed to carry threedifferent groups on its surface, namely, nine azide (purple circles), nineamine (red circles), and fifty-four terminal acid groups for controlledconjugation of targeting ligands, imaging agents, or therapeutic agents.Reproduced with permission from ref 23. Copyright 2011 AmericanChemical Society.



doxorubicin, docetaxel, cisplatin, and angiostatic drugs such asanginex or endostatin have been encapsulated for therapeuticactivity.8,34−36 Most recently, the principle of multifunctionalityhas been pushed far with the construction of a liposomecontaining Gd-DOTA-lipid for MRI, a lipidized near-infrared(NIR) dye for NIR fluorescence imaging, DOX loading fortherapeutic activity, and radiolabeling with 99m-Tc and 64-Cufor SPECT and PET imaging. These liposomes were applied invivo to a squamous cell carcinoma of head and neck (SCCHN)tumor xenograft in nude rats after intratumoral injection.37 Inthis approach the curiosity of what can be done with thistheranostic construct seems to have overtaken concerns aboutreproducibility, scalability, and monodispersity of the product,all qualifiers for the translation into the clinic and to thepatients, and costs of goods, an important index for anypharmaceutical company considering this potential product.Liposomes are metastable assemblies in which lipid

molecules can migrate (“flip-flop”) between the inner andouter half-layers of the lipid membrane, potentially causingleakiness, and fusion and fission of liposomes have beenobserved, all caused by the mobility of lipid molecules and allpotential sources of polydispersity within a theranosticformulation. This mobility is vastly reduced for oligomeric orpolymeric molecules, which also can self-assemble to formliposomes or vesicles. Polymeric liposomes or polymersomesare a more recent variation of liposome nanocarriers.Polymersomes offer essentially the same features as liposomesand, therefore, have triggered the same expectations astheranostic nanocarriers capable of encapsulating (multimodal)diagnostic and therapeutic agents, and accommodatingreceptor-specific ligands on their surfaces for active target-ing.38,39 Polymersomes have been loaded with doxorubicinwithin their hydrophobic membranes and with either hydro-phobically modified SPIOs within the membrane or unmodifiedSPIOs within the aqueous core.40,41 Wormlike polymersomeshave been formed, stabilized by cross-linking of PEG-methacrylate segments at the inner membrane layer, andspiked with folic acid ligands conjugated to the PEG coblock ofthe constituent polymers at the outer layer. Polymersomeuptake and cytotoxicity was observed using HeLa humancervical tumor cells.41 This last example demonstrates anotheradvantage of polymersomes over liposomes besides improvedstability, i.e., the ability to design desired elements into thepolymer chain, in this case methacrylate groups conjugated toshort PEG-46 (repeat units) and FA conjugated to long PEG-114. During the self-assembly process the polymer chainsaligned with the longer PEG at the outside and the shorter PEGon the inside of the polymersome membrane. Considering theimmense progress achieved with polymerization processes,resulting in polymers with designable structures and lowpolydispersity, one can imagine extending the design approachto incorporate functional groups along the polymer chain thatallow conjugation of drug molecules (i.e., DOX) and MRIagents (i.e., functionalized SPIOs or Gd-chelates) onto thechain in controlled fashion similar to the dendrimer designdiscussed earlier (see Figure 2B). These polymers can bepurified and characterized prior to self-assembly into polymer-somes. One possible example is shown in Figure 3. Thismodular approach would vastly reduce the risk of polydispersitycompared to random loading or surface modification ofpreformed nanocarriers currently applied, potentially simplify-ing the regulatory approval process. Looking at the approvedliposome formulations on the market, one has to acknowledge

the simplicity of their composition, which does not carry muchrisk for polydispersity: lipid membranes, for some productscovered with PEG chains, the core filled with a drug, and celluptake relying on the EPR effect. Adding more components tothe liposome payload will increase the risk of polydispersity,and adding active targeting ligands could complicate thebiological behavior because of multivalency as outlined earlier.

3.3. Polymeric Micelles. Polymeric micelles are related topolymersomes in that they also are formed through self-assembly of block copolymers. However, micelles have ahydrophobic instead of an aqueous core because theconstituent copolymers are composed of hydrophilic−hydro-phobic diblock instead of hydrophilic−hydrophobic−hydro-philic triblock copolymers. The different structure of polymericmicelles generally leads to smaller size range of 20−60 nmcompared to polymersomes, which might give these nano-carriers a competitive advantage considering that someresearchers believe the “sweet spot” for EPR-driven tumorcell uptake is around 40−60 nm. Although only one polymericmicelle formulation is on the market (Genexol-PM for thedelivery of paclitaxel, approved in Korea in 2007), there areseveral formulations in advanced clinical trials in Japan and theU.S., incorporating drugs such as Adriamycin, paclitaxel, SN-38,cisplatin, and DACHPt (activated oxaliplatin). In order toexpand the concept to theranostics, a polymeric micelleformulation composed of PEG-poly(glutamic acid), DACHPt,and the MRI agent Gd-DTPA (Magnevist) has been developedand tested in an orthotopic animal model of intractable humanpancreatic cancer. DACHPt and Gd-DTPA were associatedwith the polymeric backbone through reversible metal chelation

Figure 3. Example of modular approach to functionalized polymers,providing branched conjugation points for attachment of diagnostic(1) and therapeutic (2) agents and terminal functionalities on PEGsegments for targeting (3) or cross-linking (4) groups, as well as key-lock functionality (5) for selective coupling of both polymer segments.Both chain modules can be purified and analyzed prior to coupling.Self-assembly would then form polymersomes of reduced polydisper-sity.



between Pt and carboxylate groups. Microsynchrotron radiationX-ray fluorescence spectrometry scanning of animal lesionsconfirmed that both drug and imaging agent colocalized in thetumor interior.42 Other approaches to fit polymeric micelleswith imaging agents include entrapment of lead sulfide (PbS)and cadmium selenide (CdSe) quantum dots, as well as theconjugation of perfluorinated aliphatic chains to PEG for 19-F-MR imaging.43−45 Interesting approaches to uniform and stablemicelle nanocarriers involve the use of branched or porphyrincore molecules, which are fitted with hydrophobic−hydrophilic(PEG) copolymers. One micelle approach further containeddoxorubicin conjugated to the hydrophobic polymer segmentvia an acid-labile hydrazone linker. The PEG segments carriedeither cRGD for integrin targeting or 64-Cu chelate for PETimaging.46 Another approach contained entrapped paclitaxel asthe drug, and alkynyl-DOTA-Gd as imaging agent, conjugatedto the polymer chains by “click” chemistry.47 A third approachutilized a porphyrin core for fluorescence imaging andentrapped paclitaxel.48 Using (hyper)branched or cyclic coremolecules will stabilize micelles and reduce the polydispersityresulting from self-assembly. Especially the last three examplescarry elements that should help clinical translation becausebranched cores can improve the uniformity of nanocarrier sizes,and conjugation of active agents to the polymer chains reducespolydispersity. Interestingly, only one approach involvedconjugation of imaging and therapeutic agent to the polymer.A very insightful review of the potential of polymeric micelles astheranostic nanomedicine has been provided recently byKataoka et al., a strong promoter of this class of nanocarriers.49

However, the same concerns directed at polymersomes holdtrue for polymeric micelles, except that the diblock copolymerstructure in micelles could simplify chemical functionalizationof these polymers, leading to reduced costs of goods.3.4. Polymeric Nanoparticles. Polymeric nanoparticles

are closely related to polymeric micelles, in fact someresearchers refer to micelles as nanoparticles.50,51 However,the difference between these two nanocarriers, at least for thisdiscussion, is the fact that micelles form via self-assembly whilenanoparticle formation requires a process, usually mixingbetween a solution and an antisolvent. This process of forcednanoparticle precipitation allows more flexibility for thepolymer chains used in this application and for theirfunctionalization. Intermolecular attraction, usually based onthe hydrophobic polymer segments in water, has to besubstantial in order to form and maintain micelles; however,nanoparticles can form even with weaker attractive interactionbetween the constituent polymers as long as the forces arestrong enough to preserve the nanoparticles after formation.The considerations and challenges for random entrapment ofdiagnostic and therapeutic agents or their conjugation topreformed nanoparticles are the same as for polymersomes andpolymeric micelles. Concepts based on these routes result oftenin poor reproducibility and high polydispersity of nanoparticlecomposition and, therefore, will not be further discussed;instead examples describing more specific approaches tosynthesize polymers, functionalize them for theranosticapplications, and assemble them to nanoparticles will bepresented in support of the modular approach exemplarilyshown in Figure 3. Water-soluble glycol chitosan waschemically modified with hydrophobic 5β-cholanic acid inorder to tailor its hydrophobicity, and conjugated with the NIRfluorescence (NIRF) dye Cy5.5 as diagnostic agent. Thispolymer formed nanoparticles in water, which were loaded with

paclitaxel via encapsulation. Tumor uptake and drug releasewere monitored by NIRF using SCC7 tumor-bearing mice.52 Inanother approach, an oligo(ethylene amine) polymer contain-ing secondary amines was conjugated to the lanthanide-bindingchelate diethylenetriamine pentaacetic acid (DTPA). Theamines are protonated at physiological pH and promotebinding and compaction of nucleic acids into polyplexes, whilethe lanthanide-binding domain can be chelated with eithergadolinium (Gd), a MRI contrast agent for submicrometer tomillimeter scale imaging, or luminescent europium (Eu) forvisualization on the nanometer to micrometer scale, which canbe imaged with fluorescence microscopy. Plasmid DNA(pDNA) transfection studies performed on polyplexes revealedthat the Gd(III)-containing analogues show high imagecontrast compared to nontransfected cells, and that Eu(III)analogues can be imaged with fluorescent microscopy insidecells.53 In both examples, functionalization of the polymers withthe diagnostic agent is controlled, while loading of thetherapeutic active is still random and can lead to polydisperseproducts. Lipoproteins and synthetic analogues have beenstudied as theranostic agents. Lipoproteins are ideal for thedelivery of cancer drug and imaging agents since they haveevolved to circulate in the bloodstream for a significant amountof time. Lipoprotein nanoparticles are highly amenable tosurface conjugation, while the hydrophobic core facilitates thephysical entrapment of poorly water-soluble drugs or imagingagents. The applications of this natural nanoparticle haverecently been reviewed.54 A very interesting approach tomagnetic nanoparticles with controlled doxorubicin (DOX)content involves chemical polymerization of PEG, DOX,dopamine (DA), and di(ethylene glycol) diacrylate to form abiodegradable and pH-sensitive poly(beta-amino ester)(PBAE) copolymer of known composition. This copolymerwas then mixed with oleic acid-capped iron oxide nanoparticlesand formed the desired magnetic nanoparticles (NP-DOX) vialigand exchange reaction. Cell uptake and efficacy of NP-DOXversus free DOX was demonstrated in drug resistant C6-ADRcells.55 This approach elegantly combines controlled chemicalsynthesis, leading to a well-defined polymer product, withnanoparticle formation around 12 nm SPIO cores, greatlyreducing the size polydispersity observed during self-assembly.The ratio between diagnostic and therapeutic agents can becontrolled through the conjugation density of DOX along thePBAE backbone. Similarly, carboxymethylcellulose was acety-lated and conjugated with docetaxel and PEG chains. Thisfunctionalized polymer was then mixed with SPIO nano-particles to give theranostic nanoparticles.56 This simplifiedapproach, however, comes at the cost of reduced control overthe drug-to-PEG ratio per polymer strand. In a related study, abiodegradable polymer was synthesized which included thephotosensitizer [2-devinyl-2-(1-hexyloxyethyl) pyropheophor-bide]-acrylamide (HPPH) as a part of the monomer mixture.Polymeric nanoparticles were formed via water−oil emulsionapproach; then a cyanine dye for imaging was conjugated tosurface and internal functionalities of the nanoparticles,followed by surface conjugation of PEG chains and a targetingF3 peptide. The 44 nm nanoparticles were tested in vitro forcell uptake, imaging, and photodynamic therapy (PDT)activity.57 Another interesting theranostic polymer synthesisinvolves the conjugation of three modules to form the polymer:(i) the prodrug-activating enzyme bacterial cytosine deaminase(bCD) for conversion of the nontoxic prodrug 5-fluorocytosine(5-FC) to cytotoxic 5-fluorouracil (5-FU); (ii) a poly(L-lysine)



segment carrying the NIR fluorescent probe Cy5.5; and (iii)branched poly(ethylene imine) (PEI), carrying conjugatedrhodamine dye and DOTA chelate for complexation of 111-Inas well as a functional group for the attachment of PEG. Thesemodules can be synthesized and purified prior to conjugation toform the functionalized polymer strand. Nanoparticle formationwas achieved through complexation between siRNA and thePEI module of the polymer.58 This approach requires anextended amount of medicinal chemistry work; however, this isno new territory for the pharmaceutical industry. The authorsclaim that this modular nanoparticle approach, targeted toprostate cancer in the proof-of-concept study, can be modifiedfor other cancer applications by choosing different modules.The only module prone to polydispersity in this approachseems the PEI segment, carrying three different groups.Chemical conjugation as binding mode for diagnostic andtherapeutic agents was replaced in another approach by stablehost−guest interactions. The ring compound cucurbit[6]uril(CB[6]) was conjugated to a biocompatible and biodegradablehyaluronic acid (HA) backbone. This CB[6]-HA polymer wasdecorated with modified FITC for imaging and a modifiedmodel drug via inclusion into the CB[6] moieties.59 Whilethere is an advantage in using stable host−guest interactionsover chemical conjugation for sensitive diagnostic ortherapeutic agents, this specific approach, unfortunately, relieson the same interaction for both guests, making themodification with these agents rather random. CB[6] is amember of a family of host molecules of different ring sizes,cucurbit[n]uril (n = 5−8), and therefore, it should be possibleto modify the HA backbone with two different CB[n] hostmolecules to differentiate between diagnostic and therapeuticguest interaction.

4. CONCLUSIONSTheranostics: Are we there yet? The answer, not surprisingly,can only be no. However, there are promising approaches tomove theranostic agents closer to the clinic. The design ofprodrugs and polymers carrying defined amounts of conjugateddiagnostic and therapeutic agents is possible, and severalexamples have been discussed here. The opposing concen-tration needs in diagnosis and therapy can be controlled duringsynthesis of these entities. Progress in polymer synthesis andquantitative and irreversible reactions for conjugation (e.g.,“click” chemistry) provide ample opportunities to tailorpolymers and prodrugs to the needs of the desiredapplication.60 Polydispersity of these entities can be controlledand kept sufficiently low. However, these approaches would notaddress the opposing timelines of diagnosis and therapy, andtherefore, diagnostic agents have to be biocompatible or safelycontained in chelates or complexes during their residence timein the body. Small molecule prodrugs have the advantage thatregulatory agencies are used to this kind of molecule, but rapidrenal clearance is a serious challenge. Polymers, on the otherhand, are not subjected to fast renal clearance but have to avoidhigh molecular weights (>40,000 Da) which could preventclearance from the body, or they have to be biodegradable. Thisdegradability is often achieved through ester bonds, which arehydrolyzed under low pH or in the presence of enzymes;however, polyester degradation creates free acid groups whichcan reduce the local pH to deleterious levels and potentiallydestroy acid-labile diagnostic and therapeutic agents.61 This isclearly something to keep in mind when designing function-alized polymers. These designed polymers can self-assemble

into polymersomes or polymeric micelles, depending on theirstructure, or they can be forced to assemble into polymericnanoparticles by solvent/antisolvent precipitation. Nanocarrierpolydispersity is an issue for clinical translation and regulatoryapproval of nanocarriers. This polydispersity can be reduced by(i) purified and well-designed constituent polymers; (ii) thepresence of cyclic or hyperbranched cores around which thenanocarriers can form; (iii) the presence of well-defined metaloxide (e.g., SPIOs) nanoparticles that attract these polymersand support the nanocarrier structure; or by controlled mixingand precipitation conditions in the case of nanoparticles.Alternatively, nanocarriers can be shaped and formed byspecific processes such as PRINT.62 The application ofcombinatorial design approaches might offer another route todesign not only the constituent polymers but also the resultingnanocarriers.63 Random entrapment and surface conjugation ofdiagnostic and therapeutic agents into liposomes, polymer-somes, micelles, and nanoparticles is a tempting and easilyachievable approach. However, the polydispersity of theresulting nanocarriers and questionable reproducibility of theapproach will create high hurdles for clinical translation andregulatory approval. The question needs to be asked how mucheffortand research fundingshould still go into theserandom approaches given that the literature does not showencouraging outcomes compared to the more tedious butcontrollable synthetic approaches with subsequent particleformation.Another question needs to be asked: How important are

targeting ligands in nanocarrier-based delivery? Adding activetargeting ligands to a nanocarrier not only adds at least anotherstep to its production but also adds to polydispersity,complicates regulatory evaluation and approval, increases thecosts of goods, and can have negative biological outcomesbecause of multivalency-binding and enhanced recognition bythe MPS with reduced circulation time. Unlike small moleculeswhere adding a targeting ligand makes sense to reduce thevolume of distribution (Vd), nanocarriers in the size range of 10to 100 nm (or somewhat higher) are subjected to the EPReffect. One should keep in mind that of the 41 nanocarrier-based formulations that have translated to the market or areunder investigation at different levels of clinical development,37 rely on passive targeting through the EPR effect. Only fouractively targeting nanocarriers are in clinical development, oneusing the PSMA and three using the transferrin receptor as thetarget.5 One last cautious comment should be added. The U.S.Food and Drug Administration (FDA), in an attempt toprevent companies from making a simple ester prodrug from amarketed product and claiming this prodrug as a new chemicalentity (NCE) although the prodrug will readily convert back tothe original drug after application, will not accept ester bondsbetween drug and carrier as a new entity.64 This is potentially aproblem for the commercial development of nanocarrier-baseddelivery of drugs and theranostics because ester bonds are thepreferred mode of delivery and intratumoral drug release. Onehas to keep this challenge in mind when designing theranosticnanocarriers and hope that the FDA will eventually acknowl-edge that these complex new agents are not the same as asimple ester prodrug.

■ AUTHOR INFORMATIONCorresponding Author*E-mai l: ssvenson@drugdeliverysolut ion.com. Tel:781.316.0065.



mailto:[email protected]

NotesThe authors declare no competing financial interest.

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theranostics: are we there yet?

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