三阴性乳腺癌
前药
体内
医学
乳腺癌
细胞毒性
化疗
转移
转移性乳腺癌
癌症研究
耐受性
药理学
内科学
化学
癌症
体外
生物
生物化学
不利影响
生物技术
作者
Ran Wei,Xiaoyu Liu,Lu Chang,Ying Cai,Chao Zheng,Jia Liu,Yaping Li,Pengcheng Zhang
标识
DOI:10.1016/j.jconrel.2019.12.027
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI