EDITORIAL H E A LT H C A R E

Engineering precision

Giovanni Traverso is an Instructor of Medicine, Division of Gastroenterology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA. E-mail: ctraverso@ partners.org

Robert Langer is an Institute Professor at the Massachusetts Institute of Technology, Cambridge, MA 02139, USA. E-mail: [email protected] Citation: G. Traverso, R. Langer, Engineering precision Sci. Transl. Med. 7, 289ed6 (2015).

CREDIT: MGH PHOTO (G.T.); BACHRACH (R.L.)

10.1126/scitranslmed.aab1943

PRESIDENT OBAMA’S RECENT ANNOUNCEMENT HERALDED A NEW INITIATIVE to accelerate scientific advances in precision medicine–therapy that takes a targeted approach tailored to each patient and his or her disease. Initial efforts will focus on cancer research, with a view to addressing a broader spectrum of diseases and enhancing our knowledge of human physiology and pathophysiology. Thus, resources allocated to this initiative will benefit patients, clinicians, and researchers alike. Innovations in engineering sciences will play a vital role in delivering precision medicine to the bedside. Here, we describe new technologies that could help facilitate the translation of precision medicine to patients. Optimizing chemotherapy using sensitivity analyses. Genomics has revolutionized the rational design of targeted therapies. A critical advance would be the ability to evaluate the effect of chemotherapies within the tumor microenvironment at the individual-tumor level and to use the information to guide a patient’s therapy by selecting treatments that have the greatest impact on disease burden. Technology exists to perform such studies with explanted tumor cells from patients in scaffolds that mimic in vivo conditions. Future iterations of this technology might make in vivo testing possible. Such technologies might be most relevant in cases of advanced disease wherein tumors have stopped responding to standard therapies and treatment opportunities are limited. Optimization of therapeutic combinations also requires an understanding of the effects of drug-release kinetics (for example, continuous versus pulsatile delivery) to effectively target cancer cell growth and metastasis as well as the microenvironment. We may not be far from a vision of cancer therapy in which we can determine a tumor-specific optimal course of treatment by performing something akin to antibiotic sensitivity analysis on tumor cells. If such assays are performed in threedimensional scaffolds, testing would also take into account the multiple effects of the tumor microenvironment on treatment efficacy. Toward personalized pharmacokinetics. Two other major enhancements that engineering can help to reach clinical reality are technologies that enable remote triggering for drug release (1) and subsequent closed-loop systems in which the sensing of an analyte triggers the release of a therapeutic. Such systems promise the ability to reach beyond individualized chemotherapy to achieve personalized pharmacokinetics, which already has been recognized as a way to increase treatment benefits (2). These personalized technologies can be fully realized as “smart” matrices or sensors (3) coupled to drug depots that autoregulate release on the basis of drug concentrations in the patient’s blood in order to constantly maintain the desired serum levels. Sensors can also be built to trigger release by remote control on the basis of tumor response to therapy or other clinical factors. Companion diagnostics for precision therapies. Point-of care diagnostics for the rapid evaluation of chemotherapy sensitivities (as predicted by mutations and protein biomarkers) (4) could enable the immediate deployment of precise depot systems that provide localized high-concentration therapeutics directly to tumors. Such technologies in combination with extended release or externally triggerable devices would enable deployment of specific drug combinations in the tumor bed to aid in treatment of unresectable tumors. Nanotechnology for targeted therapies. Nanoparticles, with their large surface area– to–volume ratio, provide many advantages for drug delivery. Nanoparticles can facilitate entry into cells, can have long circulating times, can be used to target drug delivery to tissues with selected characteristics, and then can slowly release their therapeutic content. Moreover, coating nanoparticles with poly(ethylene)-glycol can impart stealth ability to evade attack by the immune system, and decorating them with targeting moieties can provide more precise effects on target tissues while minimizing potential toxicity from effects on nontarget tissues. For example, nanoparticles loaded with docetaxel and targeted to the prostate-specific membrane antigen have been tested in humans with promising results (5). Future nanopayloads enabling significantly greater precision are likely to include targeted www.ScienceTranslationalMedicine.org   27 May 2015   Vol 7 Issue 289 289ed6     1

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“I want the country that eliminated polio and mapped the human genome to lead a new era of medicine—one that delivers the right treatment at the right time.” –U.S. President Barack Obama in the 20 January 2015 State of the Union

EDITORIAL delivery of nucleic acids, including small interfering RNAs, microRNAs, and systems for gene editing that carry the promise of extreme molecular precision, thus ushering in a new generation of therapeutics (4). TAKE YOUR MEDICINE! As the precision medicine initiative gets under way and engages patients and research subjects, it is imperative to devote resources to addressing the challenging and pervasive problem of medication nonadherence. Failure to stick to a therapeutic regimen can thwart even the most cleverly engineered medical treatment plans. Nonadherence to chronic medications is estimated to be ~50% in developed nations and even lower in the developing world—and is estimated to result in costs in excess of $100 billion per year in the United States alone (6). Whereas there has been great excitement about the increase in orally administered anticancer treatments over the past decade, even in oncology, nonadherence ranges from 16 to 100% (7). Engineering approaches designed to improve medication adherence include the development of new drug formulations and delivery devices for extended release, so that a single administration event could provide a much longer course of treatment (8). Key to delivering on President Obama’s promise of precision medicine is that all of the advancements in personalized and targeted therapies are, in fact, delivered to patients.

1. R. Farra, N. F. Sheppard Jr., L. McCabe, R. M. Neer, J. M. Anderson, J. T. Santini Jr., M. J. Cima, R. Langer, First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra21 (2012). 2. C. L. B. Kline, A. Schiccitano, J. Zhu, C. Beachler, H. Sheikh, H. A. Harvey, H. B. Mackley, K. McKenna, K. Staveley-O’Carroll, L. Poritz, E. Messaris, D. Stewart, J. Sivik, W. S. El-Deiry, Personalized dosing via pharmacokinetic monitoring of 5-fluorouracil might reduce toxicity in early- or late-stage colorectal cancer patients treated with infusional 5-fluorouracil-based chemotherapy regimens. Clin. Colorectal Cancer 13, 119–126 (2014). 3. S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013). 4. R. Langer, R. Weissleder, Nanotechnology. JAMA 313, 135–136 (2015). 5. J. Hrkach, D. Von Hoff, M. M. Ali, E. Andrianova, J. Auer, T. Campbell, D. De Witt, M. Figa, M. Figueiredo, A. Horhota, S. Low, K. McDonnell, E. Peeke, B. Retnarajan, A. Sabnis, E. Schnipper, J. J. Song, Y. H. Song, J. Summa, D. Tompsett, G. Troiano, T. Van Geen Hoven, J. Wright, P. LoRusso, P. W. Kantoff, N. H. Bander, C. Sweeney, O. C. Farokhzad, R. Langer, S. Zale, Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4, 128ra39 (2012). 6. D. M. Cutler, W. Everett, Thinking outside the pillbox—Medication adherence as a priority for health care reform. N. Engl. J. Med. 362, 1553–1555 (2010). 7. K. Ruddy, E. Mayer, A. Partridge, Patient adherence and persistence with oral anticancer treatment. CA Cancer J. Clin. 59, 56–66 (2009). 8. G. Traverso, R. Langer, Perspective: Special delivery for the gut. Nature 519, S19 (2015).

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– Giovanni Traverso and Robert Langer