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Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer

Nature Reviews Clinical Oncology volume 13, pages 750–765 (2016)Cite this article

Subjects

Key Points

  • A nearly impenetrable stroma and hypovascularity limit drug delivery to pancreatic ductal adenocarcinoma (PDAC) cells and thus the effectiveness of treatments, resulting in a very poor prognosis for patients

  • Various nanoparticle-based approaches to overcome the biological barriers to drug delivery that are characteristic of pancreatic cancer are being explored in order to improve patient responses and outcomes

  • Nanoformulations comprising albumin-bound paclitaxel (nab-paclitaxel) and liposomal irinotecan (MM-398) are approved for the treatment of PDAC based on survival benefits of 1.8–1.9 months

  • Various signalling pathways (for instance, the MAPK/PI3K, Hedgehog, and autophagy cascades), and the KRAS oncogene are involved in the progression of pancreatic cancer and could serve as alternative therapeutic targets

  • Strategies to overcome pathophysiological barriers and normalize the tumour matrix (such as Hedgehog-pathway inhibitors) can relieve the solid stress and improve vessel perfusion to increase nanoparticle penetration of the tumour

  • Attributes of nanomedicine, such as small size, a high degree of drug encapsulation, and controlled drug release, can improve drug delivery to the tumour by exploiting novel endocytic routes that are independent of membrane transporters

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer- related deaths. PDAC remains one of the most difficult-to-treat cancers, owing to its unique pathobiological features: a nearly impenetrable desmoplastic stroma, and hypovascular and hypoperfused tumour vessels render most treatment options largely ineffective. Progress in understanding the pathobiology and signalling pathways involved in disease progression is helping researchers to develop novel ways to fight PDAC, including improved nanotechnology-based drug-delivery platforms that have the potential to overcome the biological barriers of the disease that underlie persistent drug resistance. So-called 'nanomedicine' strategies have the potential to enable targeting of the Hedgehog-signalling pathway, the autophagy pathway, and specific RAS-mutant phenotypes, among other pathological processes of the disease. These novel therapies, alone or in combination with agents designed to disrupt the pathobiological barriers of the disease, could result in superior treatments, with increased efficacy and reduced off-target toxicities compared with the current standard-of-care regimens. By overcoming drug-delivery challenges, advances can be made in the treatment of PDAC, a disease for which limited improvement in overall survival has been achieved over the past several decades. We discuss the approaches to nanomedicine that have been pursued to date and those that are the focus of ongoing research, and outline their potential, as well as the key challenges that must be overcome.

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Figure 1: Critical signalling pathways involved in PDAC pathogenesis.
Figure 2: Strategies to overcome the pathophysiological barriers impeding the effectiveness of treatments of PDAC.

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Acknowledgements

The authors thank Dr Stephan T. Stern and Dr Jennifer H. Grossman for their critical review of the manuscript, and Allen Kane of Leidos Biomedical Research for assistance with graphic illustrations. The work of P.P.A., R.M.C., and S.E.M. has been funded, in whole or in part, by Federal funds from the Frederick National Laboratory for Cancer Research, US NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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  1. Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, 21702, Maryland, USA

    Pavan P. Adiseshaiah, Rachael M. Crist & Scott E. McNeil

  2. Office of the Director, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Sara S. Hook

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  1. Pavan P. Adiseshaiah
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P.P.A. researched the data for the article and wrote the manuscript. R.M.C. assisted with drafting of the manuscript. All authors contributed to discussions of content and reviewed and/or edited manuscript before submission.

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Correspondence to Pavan P. Adiseshaiah.

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P.P.A., R.M.C, and S.E.M. are employees of Leidos Biomedical Research, the operations and technical support contractor for the Frederick National Laboratory for Cancer Research. S.S.H. declares no competing interests.

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Adiseshaiah, P., Crist, R., Hook, S. et al. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol 13, 750–765 (2016). https://doi.org/10.1038/nrclinonc.2016.119

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