EDITORIAL

Theranostic nanomedicine for cancer

Baran Sumer1, Jinming Gao2†

†Author for correspondence1Department of Otolaryngology, Head and Neck Surgery, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USATel.: +1 214 648 3102;Fax: +1 214 648 2246;E-mail: baran.sumer@utsouthwestern.edu 2Department of Pharmacology, Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75093, USATel.: +1 214 645 6370;Fax: +1 214 645 6347;E-mail: jinming.gao@ utsouthwestern.edu

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‘Over recent decades, there has been explosive development of a

variety of nanotechnology platforms to diagnose and

treat cancer.’

With over 10 million new cases per year world-wide, cancer remains a difficult disease to treatand a significant cause of morbidity and mortal-ity. Over recent decades, there has been explosivedevelopment of a variety of nanotechnologyplatforms to diagnose and treat cancer [1,2].These nanoplatforms, including polymer–drugconjugates, liposomes, polymeric micelles, den-drimers, polymersomes and Au/Si/polymershells, have been established with distinctivechemical compositions and physical properties.Compared with traditional molecular-basedcontrast agents or therapeutic drugs, this newnanomedicine paradigm enables a highly inte-grated design that incorporates multiple func-tions, such as cell targeting, ultra-sensitiveimaging and therapy, in one system. Multi-functional nanomedicine holds considerablepromise as the next generation of medicine thatenables the early detection of disease, simultane-ous monitoring and treatment and targeted ther-apy with minimal toxicity. This editorial willfocus on the emerging concept of multi-functional theranostic nanomedicine and theopportunities it provides for combating cancer.

Therapeutic challenges of cancerClinicians have long realized that cancer repre-sents a heterogeneous population of diverse dis-eases. More recent advances have shed furtherlight on the molecular heterogeneity foundbetween cancers of the same type, between a pri-mary tumor and its metastatic foci and evenbetween the cells that constitute individualtumors. Because a multitude of cancer pheno-types exist within a given tumor, even beforetherapy, there is ample opportunity for subpopu-lations of cancer cells to evade monotherapy.This molecular diversity, combined with theselection of resistant phenotypes of cancer cells

2008 Future Medicine Ltd ISSN 1743-5889

with treatment, is a major challenge in the treat-ment of this disease. Because cancer cells evolvein response to the selection of therapy, the goalof eradicating all cells within a tumor by target-ing a specific pathway unique to cancer cellsbecomes a Herculean task. When this task is notcompleted, the cells that do not respond tochemotherapy can then grow and reconstitutethe tumor in the body.

Theranostic nanomedicineTumor heterogeneity and adaptive resistanceremain formidable challenges to therapy. Treat-ment of cancer requires the ability to addressthese two intrinsic properties of this complex dis-ease. Theranostics was coined originally as a termto describe a treatment platform that combines adiagnostic test with targeted therapy based on thetest results [3]. Here, we define theranostic nano-medicine as an integrated nanotherapeutic sys-tem, which can diagnose, deliver targeted therapyand monitor the response to therapy. This inte-gration of diagnostic imaging capability withtherapeutic interventions is critical to addressingthe challenges of cancer heterogeneity and adap-tation. Molecular diagnosis by imaging is usedfirst to characterize the cellular phenotypespresent in each tumor to guide target-specifictherapy. Both intra- and intertumor heterogene-ity make this an essential component of therapythat will take us beyond the era of ‘one-size-fits-all’ generic medicine to truly personalized medi-cine. Because cancer is a highly heterogeneousdisease, our treatments will probably have to beas diverse. Furthermore, this characterization oftumors cannot simply be analysis of a physicalbiopsy specimen; the heterogeneity of the cellswill make such a sampling prone to error thatwill fail to give a full description of the pheno-typic breadth that exists within a tumor. It willalso fail to characterize cells that have metasta-sized to other locations. All of the tumor cellsthroughout the body must be subjected tomolecular characterization, which can only beperformed efficiently through full-body imaging.

After molecular diagnosis, the ability to targetthe identified molecular markers to eradicate allof the diverse phenotypes of cancer is imperative.

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As a platform technology, nanomedicine has theadvantage of being able to target multiple tumormarkers and deliver multiple agents simultane-ously for synergy in addressing the challenges ofcancer heterogeneity and adaptive resistance.

Even with a full molecular profiling andmultitargeted therapy based on this profile, thetask of eradicating all cancer cells within a givenpatient would not be over. The tumor inevitablyevolves in response to even multitargeted ther-apy, therefore, the molecular analysis of thetumor must be repeated quickly and the resultsused to intelligently modify the treatment andtargeting strategy. This real-time, adaptivetargeting is the final essential component oftheranostic nanomedicine to address adaptiveresistance of cancer cells.

‘This molecular diversity, combined with the selection of resistant phenotypes of cancer cells with treatment, is a major

challenge in the treatment of this disease.’

This is the challenge and the technology todevelop platforms that can address these complexproperties of cancer is gradually coalescing withinput from a range of diverse fields in cancer bio-logy, drug delivery, molecular imaging, materialsscience and clinical oncology. Here, we provide abrief overview of a few important directions inthe development of theranostic nanomedicine.

Zoom in on new cancer targetsConventional chemotherapy seeks to exploit thedifferences between cancer cells and normal cells.Typically, these differences are limited to globalcharacteristics of cancer cells, such as rapid prolif-eration. Cisplatin, for example, is a traditionalchemotherapeutic drug that affects rapidly divid-ing tumor cells preferentially by crosslinkingDNA and interfering with its synthesis and repair.Unfortunately, these drugs are also highly toxicand create considerable morbidity in patients.Dosage for these drugs is limited by systemic tox-icity and tumors can become resistant to themrapidly by nonspecific processes, such as activetransport of the drug out of the cancer cells. Newdrugs that can provide larger therapeutic indicesare greatly needed.

Thanks to advances in cancer biology, a pleth-ora of novel cancer-specific targets are being char-acterized, including cancer-specific enzymes andreceptors, changes in signal transduction path-ways, angiogenesis-related receptor expression, as

well as alterations in replication, repair, trans-lation, transcription, post-synthetic modificationand chromosome-regulatory processes. Screeningof compound and phage libraries has also led tothe discovery of many new therapeutic agentsand targeting ligands with high binding affinityand specificity. Recently, agents that targetmolecular markers unique to cancer cells, such asmonoclonal antibodies, have been approved toreduce systemic toxicity by achieving targetedtherapy. However, targeted agents can, by theirvery precision, enable cancer cells to bypass tar-geted pathways and can develop stronger resist-ance than older chemotherapeutic agents. A goodexample of this is found in breast tumors withHer2/neu expression, where treatment withHerceptin® causes resistance over time by usingpathways that bypass the Her2/neu receptor.Administration of a combination of monoclonalantibodies to multiple receptors, however, effec-tively reduced the tumor recurrence rates [4]. Thissynergistic effect can be achieved with a singlenanomedicine formulation, by attaching differ-entially targeted peptides or antibodies to thesame nano-platform. This would reduce thecomplexity of multidrug administration. Thenano-platform can also be further engineered toprovide controlled release of cytotoxic drugs ondelivery to cancer cells. The multifunctionalnanomedicine would therefore achieve synergis-tic targeted therapy by blocking multiple recep-tors, reduce systemic toxicity by minimizingchemotherapeutic drugs in systemic circulationand achieve further synergy by combining thesedrugs with molecular targeting, and deliver thetargeted chemotherapeutic agent specifically totumors, thus improving the therapeutic index.

‘…the technology to develop platforms that can address these complex properties of cancer is gradually

coalescing with input from a range of diverse fields in cancer biology, drug

delivery, molecular imaging, materials science and clinical oncology.’

Cancer molecular imagingDrug development and imaging have becomeincreasingly intertwined in recent years owing tothe advantages of using noninvasive, high-throughput imaging studies. Almost all imagingmodalities can be used in drug studies to provideanatomic, pharmacokinetic and pharmaco-dynamic information. Current nuclear-imaging

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Theranostic nanomedicine for cancer – EDITORIAL

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methods (e.g., PET and single photon emissioncomputed tomography) offer superior sensitiv-ity compared with other modalities, such ascomputed tomography (CT), MRI and ultra-sound. However, CT and particularly MRI canprovide high-resolution images with great ana-tomical resolution and soft-tissue contrast.Consequently, multimodality imaging is emerg-ing as a powerful combination to providecomplementary information for pharmaceuticalapplications.

‘Successful development of theranostic nanomedicine requires significant

advances in materials science and nanocomposite materials.’

Imaging studies are also used increasingly toprovide molecular information in cancer applica-tions [5]. Like therapeutics, targeted delivery ofcontrast agents with a nano-platform can beachieved by functionalization of the nano-plat-form to cancer markers. By sequential function-alization of the nano-platform against differentcancer targets, the surface target expression of thewhole tumor can be mapped molecularlythrough imaging. The combination of targetsthat would enable delivery of the nano-platformto the entire tumor can then be used to function-alize the therapeutic version of the nanoparticle.In addition, codelivery of imaging contrast agentand chemotherapeutic drugs can provide real-time validation of the targeting strategy. If molec-ular targets become unavailable owing to down-regulation or saturation, imaging can be used tomap out alternate targets. Finally, molecularmarkers of cellular death can also be imaged toconfirm tumor response. These markers can bedownstream effector molecules of the drug ormolecular or cellular markers for processes, suchas apoptosis and angiogenesis. The advantage ofthis approach is that it can provide early feedbackof therapeutic efficacy before detection of tradi-tional end points, such as tumor shrinkage. Insummary, imaging can be used to track nanopar-ticles systemically, pre-validate appropriate tar-geting and track the expression pattern of surfacemarkers for adaptive targeting, as well as providereal-time information on tumor response.

Nanocomposite materialsSuccessful development of theranostic nano-medicine requires significant advances in mate-rials science and nanocomposite materials. Idealnanomedicine platforms should be small in size,

provide high drug-loading densities, be efficientin targeting to the tumor tissues with minimalnonspecific uptake, provide responsive releasemechanisms to improve drug bioavailability andalso imaging ultrasensitivity to pre-validate andmonitor therapy. Extensive studies have shownan ideal size range of 10–200 nm for sphericalnanoparticles. Achieving multifunctional designconfined within such a small size range is a chal-lenging task in the development of theranosticnanomedicine.

Recent progress has brought these goals withinreach. For example, a perfluorocarbon-basednanoparticle system (∼200nm) has been estab-lished as a tumor vascular targeting system thatcan simultaneously deliver drug molecules as wellas ultrasound and MRI contrast agents [6]. Mix-tures of nanoparticles with different perfluoro-carbon cores also provide a quantitative,multispectral signal, which can be used to dis-tinguish the relative concentrations of epitopeswithin a region of interest. Another recent studyhas demonstrated the feasibility of developingmultifunctional polymeric micelles (<100 nm indiameter) with specific cancer targeting, ultra-sensitive MRI detection and pH-sensitiverelease of drugs for cancer therapy [7]. Clusteringof hydrophobic superparamagnetic iron oxidenanoparticles in the hydrophobic micelle coreresulted in dramatically increased T2 relaxivitythat subsequently lowered the MR detectionlimit to nanomolar particle concentrations. Thispermits the detection of as few as 50,000 tumorendothelial cells that overexpress αvβ3 integrin,an angiogenic tumor marker.

‘As the capabilities of multifunctional nanoplatforms continue to increase, the integration of cancer biology, diagnostic

imaging and materials science in the future will be essential … for

cancer therapy…’

It should be noted that most current nano-therapeutic systems are developed for a limitednumber of clinically approved drugs, such aspaclitaxel and doxorubicin. For many new ther-apeutic agents with diverse physico–chemicalproperties, drug carriers need to be tailored toincrease their compatibility with these agents toachieve adequate therapeutic payload and imag-ing sensitivity. Meanwhile, controlled release ofthe encapsulated agents in tumors is critical andpresents another challenge in the developmentof these therapeutic nanocomposite materials.

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Concluding remarksDespite tremendous advances in cancer therapy,many scientific, technological and clinical chal-lenges remain that will require a highly inter-disciplinary and collaborative approach toovercome. Regulatory challenges also need to beaddressed. The current paradigm for regulatoryapproval of therapeutics might have to bealtered in the new era of multicomponent nano-medicine with modular designs that can be per-sonalized to individual patients and alteredduring therapy for adaptive targeting. Withadvances in cancer biology and explosivedevelopments in materials science and imagingtechnology, we have reason to be optimistic thatwe are at the critical threshold of a major break-through in the treatment of cancer. As the

capabilities of multifunctional nanoplatformscontinue to increase, the integration of cancerbiology, diagnostic imaging and materialsscience in the future will be essential, not justfor theranostic nanomedicine, but for cancertherapy overall.

Financial & competing interests disclosure The authors have no relevant affiliations or financialinvolvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matteror materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership oroptions, expert testimony, grants or patents received orpending, or royalties.

No writing assistance was utilized in the production ofthis manuscript.

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3. Warner S: Diagnostics plus therapy = theranostics. Scientist 18, 38–39 (2004).

4. Arpino G, Gutierrez C, Weiss H et al.: Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J. Natl Cancer Inst. 99, 694–705 (2007).

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