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Journal of Controlled Release

Journal of Controlled Release

IF: 10.5
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Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer

Published:1 February 2020 DOI: 10.1016/j.jconrel.2019.12.027 PMID: 31857101
Wei Ran , Xiaoyu Liu , Lu Chang , Ying Cai , Chao Zheng , Jia Liu , Yaping Li , Pengcheng Zhang

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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Related products
Procduct Name CAS Molecular Formula Supplier Price
Glutathione 70-18-8 C10H17N3O6S 1413 suppliers $6.00-$3580.00
Mertansine 139504-50-0 C35H48ClN3O10S 258 suppliers $20.00-$2841.00

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