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

doi:10.1016/j.jconrel.2019.12.027

	Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer
	Ran, Wei 2,3,6; Liu, Xiaoyu 2,3,7; Chang, Lu 1; Cai, Ying 2,3,6; Zheng, Chao 2,3,8; Liu, Jia 1,6; Li, Yaping 2,3,4,5,6; Zhang, Pengcheng 2,3,4,6
刊名	JOURNAL OF CONTROLLED RELEASE
	2020-02-01
卷号	318 页码:234-245
关键词	Supramolecular Self-assembly Prodrug Chemotherapy Triple-negative breast cancer
ISSN号	0168-3659
DOI	10.1016/j.jconrel.2019.12.027
通讯作者	Li, Yaping(ypli@simm.ac.cn) ; Zhang, Pengcheng(pzhang@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81671808] ; National Natural Science Foundation of China[31870995] ; National Natural Science Foundation of China[81630052] ; National Natural Science Foundation of China[81690265] ; Youth Innovation Promotion Association of CAS[2017335] ; SA-SIBS Scholarship Program
WOS关键词	CELLULAR INTERNALIZATION ; CYTOTOXIC DRUG ; DELIVERY ; PACLITAXEL ; CAMPTOTHECIN ; PLATFORM ; NANOCARRIERS ; CONJUGATE ; CARRIER ; POLYMERIZATION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000512735400021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281640]
专题	中国科学院上海药物研究所
通讯作者	Li, Yaping; Zhang, Pengcheng
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, 501 Haike Rd, Shanghai 201203, Peoples R China 4.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Shandong, Peoples R China 5.Yantai Univ, Sch Pharm, Yantai 264005, Shandong, Peoples R China 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 7.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China 8.China State Inst Pharmaceut Ind, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Ran, Wei,Liu, Xiaoyu,Chang, Lu,et al. Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer[J]. JOURNAL OF CONTROLLED RELEASE,2020,318:234-245.
APA	Ran, Wei.,Liu, Xiaoyu.,Chang, Lu.,Cai, Ying.,Zheng, Chao.,...&Zhang, Pengcheng.(2020).Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer.JOURNAL OF CONTROLLED RELEASE,318,234-245.
MLA	Ran, Wei,et al."Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer".JOURNAL OF CONTROLLED RELEASE 318(2020):234-245.