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  • Review Article
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Delivering nanomedicine to solid tumors

Abstract

Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.

Key Points

  • Enhanced permeability and retention is the primary rationale for using nanoparticles in oncology; however, only a few nanotherapeutics have been approved for the treatment of solid tumors and the overall survival benefit from these is modest in many cases

  • The abnormal structure of tumor vessels results in heterogeneous tumor perfusion and extravasation, and a hostile tumor microenvironment that fuels drug resistance and tumor progression

  • In highly fibrotic or desmoplastic tumors, the extracellular matrix consisting of an interconnected network of collagen fibers blocks penetration of large nanoparticles leaving them concentrated in perivascular regions

  • Normalization of the vascular network with antiangiogenic therapy and normalization of the extracellular matrix using matrix-modifying agents has the potential to improve the delivery and efficacy of nanomedicine

  • Targeting nanoparticles to cancer cells or tumor-associated endothelial cells is another promising strategy but may be limited by spatial and temporal heterogeneity in the expression of the targets

  • Development of nanoparticles that release therapeutic agents in response to the tumor microenvironment or an external stimulus (for example, light, ultrasound, heat, electric or magnetic fields) may also improve the delivery of nanomedicine

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Figure 1: Vascular structure and function in tumors.
Figure 2: Elevated IFP in tumors.
Figure 3: Barriers to interstitial transport of nanoparticles.
Figure 4: Effect of vascular normalization.
Figure 5: Effect of normalizing collagen matrix.
Figure 6: Mean interstitial pH and pO2 as a function of the distance to the nearest blood vessel.

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Acknowledgements

We thank L. Munn, Y. Boucher, S. Goel, V. Chahaun and B. Diop-Frimpong for their helpful comments on the manuscript. This work was supported by the National Institutes of Health (PO1-CA80124, RO1-CA126642, RO1-CA115767, RO1-CA85140, T32-CA73479), a Federal Share Income Grant, and a DoD Breast Cancer Research Innovator award (BC095991). T. Stylianopoulos was supported by a post-doctoral research fellowship from the Susan G. Komen Breast Cancer Foundation (KG091281).

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R. K. Jain and T. Stylianopoulos both contributed to researching data for the article, discussion of content and writing and editing the manuscript.

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Correspondence to Rakesh K. Jain.

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R. K. Jain reports receiving consulting fees from Astellas, AstraZeneca, Dyax, Enlight Biosciences, Genzyme, Millenium, MorphoSys, and Noxxon; lecture fees from Alnylam, Genzyme, Pfizer and Roche, and grant support from Dyax and AstraZeneca/MedImmune; and owning equity in Enlight Biosciences and SynDevRx. T. Stylianopoulos declares no competing interests.

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Jain, R., Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7, 653–664 (2010). https://doi.org/10.1038/nrclinonc.2010.139

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