Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting

Mami Murakami, Horacio Cabral, Yu Matsumoto, Shourong Wu, Mitsunobu R. Kano, Takao Yamori, Nobuhiro Nishiyama, Kazunori Kataoka

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Abstract

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

Original languageEnglish
Article number64ra2
JournalScience Translational Medicine
Volume3
Issue number64
DOIs
Publication statusPublished - Jan 5 2011

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Murakami, M., Cabral, H., Matsumoto, Y., Wu, S., Kano, M. R., Yamori, T., Nishiyama, N., & Kataoka, K. (2011). Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting. Science Translational Medicine, 3(64), [64ra2]. https://doi.org/10.1126/scitranslmed.3001385