Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Jiangbing Zhou, Toral R. Patel, Rachael W. Sirianni, Garth Strohbehn, Ming Qiang Zheng, Nha Duong, Thomas Schafbauer, Anita J. Huttner, Yiyun Huang, Richard E. Carson, Ying Zhang, David J. Sullivan, Joseph M. Piepmeier, W. Mark Saltzman

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration- approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-Approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Original languageEnglish (US)
Pages (from-to)11751-11756
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number29
DOIs
StatePublished - Jul 16 2013

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Cite this

Zhou, J., Patel, T. R., Sirianni, R. W., Strohbehn, G., Zheng, M. Q., Duong, N., Schafbauer, T., Huttner, A. J., Huang, Y., Carson, R. E., Zhang, Y., Sullivan, D. J., Piepmeier, J. M., & Saltzman, W. M. (2013). Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 11751-11756. https://doi.org/10.1073/pnas.1304504110