Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer.
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| Abstract |
Metastatic triple-negative breast cancer is one of the most devastating cancer types. Systemic chemotherapy is necessary, but its clinical performance is largely limited by severe side effects. Herein, we report a mertansine prodrug, which could self-assemble into spherical nanoparticles in water and readily convert into active mertansine at the presence of glutathione. The self-assembling mertansine prodrugs (SAMPDs) entered cancer cells via a caveolae-mediated pathway and exhibited potent cytotoxicity. The self-delivering SAMPDs did not cause hemolysis, and more importantly increased maximum tolerated dose (MTD) of mertansine by 8 folds via reducing free mertansine exposure in most of the major organs. SAMPDs improved intratumoral drug exposure and showed dose-dependent antitumor activity. When dosed at MTD, SAMPDs inhibited primary tumor growth and pulmonary metastasis by 80% and 95%, while mertansine dosed at MTD only reduced primary tumor growth and metastasis by <50% and 60%, respectively. Our results reveal the mechanism of in vivo biotransformation of self-assembling prodrug and highlight the unique advantages of self-assembling prodrug strategy in improving the efficacy and safety of chemotherapy.
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| Authors | Wei Ran, Xiaoyu Liu, Lu Chang, Ying Cai, Chao Zheng, Jia Liu, Yaping Li, Pengcheng Zhang |
| Journal | Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 318 Pg. 234-245 (02 2020) ISSN: 1873-4995 [Electronic] Netherlands |
| PMID | 31857101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2019 Elsevier B.V. All rights reserved. |
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