P-selectin is a nanotherapeutic delivery target in the tumor microenvironment

Yosi Shamay, Moshe Elkabets, Hongyan Li, Janki Shah, Samuel Brook, Feng Wang, Keren Adler, Emily Baut, Maurizio Scaltriti, Prakrit V. Jena, Eric E. Gardner, John T. Poirier, Charles M. Rudin, José Baselga, Adriana Haimovitz-Friedman, Daniel A. Heller

Research output: Contribution to journalArticle

Abstract

Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.

Original languageEnglish (US)
Article number345ra87
JournalScience Translational Medicine
Volume8
Issue number345
DOIs
StatePublished - Jun 29 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Shamay, Y., Elkabets, M., Li, H., Shah, J., Brook, S., Wang, F., Adler, K., Baut, E., Scaltriti, M., Jena, P. V., Gardner, E. E., Poirier, J. T., Rudin, C. M., Baselga, J., Haimovitz-Friedman, A., & Heller, D. A. (2016). P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Science Translational Medicine, 8(345), [345ra87]. https://doi.org/10.1126/scitranslmed.aaf7374