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Why I’m Holding onto Hope for Nano in Oncology Christine Allen Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00547 • Publication Date (Web): 12 Jul 2016 Downloaded from http://pubs.acs.org on July 13, 2016
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Why I’m Holding onto Hope for Nano in Oncology Christine Allen, Ph.D. Leslie Dan Faculty of Pharmacy, University of Toronto 144 College St. Toronto, Ontario, Canada, M5S 3M2
I’ve generally always been an optimistic person and yet, as a scientist, I have no patience for blind optimism where someone’s health is concerned. Since 2002, I have run an active research group primarily focused on the development of nanomedicines (as we now call them) for applications in oncology. I have benefited from the “nano” wave when requests for funding applications were specifically focused on the design and development of new nanomedicines and along with many of you I’ve witnessed the rise of “nano” journals and symposia and conferences focused entirely on nanomedicines. In recent months, however, “nano” has taken a real hit, in part, brought on by the struggles of BIND Therapeutics1. But, skepticism had already been brewing. Since the mid-80’s, following publication of a seminal paper by Matsumura and Maeda in Cancer Research, the design of nanomedicines for applications in oncology has been inspired by the enhanced permeability and retention (EPR) effect2. The EPR effect occurs as a result of the unique pathophysiology present at solid tumors, with the leaky vasculature leading to enhanced permeability and the compromised lymphatic drainage resulting in enhanced retention3. The long circulation lifetime of stable nanomedicines, relative to small molecules, enables exploitation of this EPR effect. As a result, the general goal in “nano” has been to design stable systems with high drug to material ratios that retain their drug while in the systemic circulation until reaching the target tumor site. In the last three decades there has been a countless number of publications on nanoparticle platforms designed to exploit EPR. Indeed, Doxil®/Pegylated Liposomal Doxorubicin (PLD) is designed to avoid normal tissues and to increase drug accumulation in the tumor, relative to administration of free drug 4, 5. For years, perhaps to our downfall, the EPR effect has been thought of as a universal approach to direct nanoparticles to tumors. It is likely for this reason that the EPR effect has recently come under scrutiny. As we have now come to appreciate cancer is highly heterogeneous. It is thus no wonder that there is also heterogeneity associated with the EPR effect. One of my favorite papers is one published by Harrington et al. in 2001 (i.e. 15 years ago!) 6. This paper reports on a study examining solid tumor accumulation of radiolabeled PEGylated liposomes in 17 patients with advanced cancers. In short, the study provides clinical evidence that the EPR effect does exist and importantly it highlights the tremendous heterogeneity in tumor accumulation of liposomes that is possible from patient to patient with the same and different cancer types. That is not to say that there is no EPR effect, rather the point is that it is variable and as a result its exploitation alone may not provide the entire solution to this disease in every patient. Dr. Maeda himself recognizes this fact as he has put forward many modulators as a means to enhance EPR 2b.
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Has “nano” failed? No. There have certainly been some failures but there are always failures. As a community we need to acknowledge the failures, learn from them and move forward. The BIND news has rocked our community but there are also success stories that must not be overlooked. Several nano-based drug formulations have been approved in recent years including Abraxane®, Marqibo® and Onivyde®. I am Canadian and we are all celebrating the success of a largely Canadian-based company, Celator Pharmaceuticals. In March 2015, Celator announced positive data from the company’s Phase 3 trial of VYXEOS® (formerly known as CPX-351) in patients with acute highrisk myeloid leukemia (AML): demonstrating significantly improved survival for patients receiving VYXEOS®7. The FDA subsequently awarded VYXEOS® breakthrough therapy designation for treatment of adults with therapy-related AML or AML with myelodysplasia-related changes7. Importantly, Celator’s unique approach is an example wherein “nano” is truly enabling a treatment strategy that would not otherwise be possible. Specifically, Celator identifies the most effective synergistic ratio of a drug combination and co-encapsulates the two drugs at this fixed ratio in a stable nanotechnology assuring delivery of this ratio to the tumor site. VYXEOS® includes cytarabine and daunorubicin co-encapsulated in a synergistic ratio within liposomes. There are also a number of other drug formulations relying on nanotechnology that have reached clinical development such as MM-302 (Merrimack Pharmaceuticals Inc., NCT01304797, NCT02213744), Cynviloq™ (NantWorks, recently completed a bioequivalence trial in the U.S., NCT02064829; marketed as Genexol-PM® in South Korea and approved for treatment of breast and non-small cell lung cancers in Korea) and NK105 (Nanocarrier Co. Ltd./Nippon Kayaku Co. Ltd. NCT01644890). Furthermore, we are seeing the integration of nanomedicines and other treatment modalities such as hyperthermia. For example, Thermodox® (Celsion Corporation) is a thermosensitive liposome formulation of doxorubicin that is currently in clinical development (e.g. NCT00826085) and relies on use of localized hyperthermia to trigger drug release. As well, building on Harrington et al.’s research and improvements in imaging hardware we are also seeing the inclusion of imaging into pre-clinical8 and clinical drug development (e.g. NCT02735798). This is an example of embracing the heterogeneity in cancer and ensuring we are able to fully exploit the benefits of nanomedicine in appropriate patient populations. The formulations that have been advanced to the clinic share in common their elegant simplicity. This is in stark contrast to some of the nanotechnologies being put forward currently, many with integrated bells and whistles, to create ‘novel’ systems and/or to achieve multifunctionality. There is of course some benefit to research that demonstrates that more complex systems can for example, overcome biological barriers or respond to internal or external stimuli as a means to enhance efficacy. We can learn from these with a goal towards designing more simple prototypes that can be scaled-up and manufactured for clinical use. Yet, we must remain mindful that ‘simple is best’ and design and complexity for sake of publication is of little benefit. A timely debate on “Nanotechnology is more Hype than Hope” recently took place at the World Biomaterials Congress (Montreal, 2016)9. I was unfortunately unable
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to attend but was able to follow a good part of the discussion via social media. From my perspective, it is certain that there has been too much hype and as a result it is difficult to meet expectations. Yet that does not mean there hasn’t been success. There has been and plenty of it and I have every confidence that this success will continue – it just may not be at the pace that we were all hoping for. On that same note, it is entirely possible that BIND Therapeutics and other companies that have struggled recently will contribute to that success. Most if not all nascent companies experience failure of one sort or another. Some don’t survive and others will. Failure is an integral part of the process of developing new technologies. The bottom line: the EPR effect exists and is heterogeneous, as is every other aspect of cancer. We have made progress and the research continues so the story is not over yet. The forward movement of nanomedicines into clinical development must be based on rock solid, comprehensive pre-clinical evidence. As scientists we need to remind ourselves of the underlying purpose of our research. It is not just about publishing papers – it is about the development of treatments that truly make a difference in patients’ lives. Unfortunately, given the incidence of cancer – prospective patients include each of us and the family, friends and colleagues we cherish. Conflict of Interest Disclosures: Christine Allen is a former employee of Celator Pharmaceuticals and was previously engaged in contract research with Merrimack Pharmaceuticals.
References: 1. Ledford, H., Bankruptcy of nanomedicine firm worries drug developers. Nature 2016, 533 (7603), 304-305. 2. (a) Matsumura, Y.; Maeda, H., A New Concept for Macromolecular Therapeutics in Cancer-Chemotherapy - Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Res 1986, 46 (12), 6387-6392; (b) Maeda, H.; Tsukigawa, K.; Fang, J., A Retrospective 30Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next-Generation Chemotherapeutics and Photodynamic TherapyProblems, Solutions, and Prospects. Microcirculation 2016, 23 (3), 173-182. 3. Maeda, H., Macromolecular therapeutics in cancer treatment: The EPR effect and beyond. J Control Release 2012, 164 (2), 138-144. 4. (a) Gabizon, A.; Catane, R.; Uziely, B.; Kaufman, B.; Safra, T.; Cohen, R.; Martin, F.; Huang, A.; Barenholz, Y., Prolonged Circulation Time and Enhanced Accumulation in Malignant Exudates of Doxorubicin Encapsulated in PolyethyleneGlycol Coated Liposomes. Cancer Res 1994, 54 (4), 987-992; (b) Laginha, K. M.; Verwoert, S.; Charrois, G. J. R.; Allen, T. M., Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res 2005, 11 (19), 6944-6949.
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5. Solomon, R.; Gabizon, A. A., Clinical pharmacology of liposomal anthracyclines: Focus on pegylated liposomal doxorubicin. Clin Lymphoma Myelom 2008, 8 (1), 21-32. 6. Harrington, K. J.; Mohammadtaghi, S.; Uster, P. S.; Glass, D.; Peters, A. M.; Vile, R. G.; Stewart, J. S. W., Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 2001, 7 (2), 243-254. 7. Celator Pharmaceuticals Website: http://www.celatorpharma.com. (accessed June 17, 2016). 8. Miller, M. A.; Gadde, S.; Pfirschke, C.; Engblom, C.; Sprachman, M. M.; Kohler, R. H.; Yang, K. S.; Laughney, A. M.; Wojtkiewicz, G.; Kamaly, N.; Bhonagiri, S.; Pittet, M. J.; Farokhzad, O. C.; Weissleder, R., Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med 2015, 7 (314). 9. World Biomaterials Congress Website: http://www.fellowsbse.org/ - !fellowsdebate-wbc-2016/u3uwq. (accessed July 8, 2016).
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