HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model

Drug Delivery

Dongyang Li¹  Tao Wang¹  Hamid Khan²  Hong Liang²  Yao Zhang²  Feng Yang²  Lei Zhao²  Yongping Li²  Zhewen Sun²  Zhenlei Zhang²  Meiling Cai²  Hongbing Sun³  Yi Gou⁴ 

[1] Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China;State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China;State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China;Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, Jiangsu, Chin;State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China;School of Pharmacy, Nantong University, Nantong, Jiangsu, China;

关键词: Albumin;    combination therapy;    drug delivery systems;    drug release;    drug resistant;   

DOI  :  10.1080/10717544.2018.1428245

来源: publisher

【 摘 要 】

Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs’ release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA–NAMI-A–Cu(BpT)Br–DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

【 授权许可】

CC BY