Self-immolative micellar drug delivery:The linker matters

作     者：Xuan Meng Min Gao Jian Deng Di Lu Aiping Fan Dan Ding Deling Kong Zheng Wang Yanjun Zhao 

作者机构：School of Pharmaceutical Science &TechnologyTianjin Key Laboratory for Modem Drug Delivery &High Efficiency and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)Tianjin UniversityTianjin 300072China State Key Laboratory of Medicinal Chemical Biology (Nankai University)Tianjin 300071China Key Laboratory of Bioactive MaterialsMinistry of EducationCollege of Life Sciences and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)Nankai UniversityTianjin 300071China 

出 版 物：《Nano Research》 (纳米研究（英文版）)

年 卷 期：2018年第11卷第12期

页      面：6177-6189页

核心收录：

学科分类：0808[工学-电气工程] 0809[工学-电子科学与技术（可授工学、理学学位）] 07[理学] 0805[工学-材料科学与工程（可授工学、理学学位）] 0702[理学-物理学] 

基　　金：the funding support from the National Basic Research Program of China the State Key Laboratory of Medicinal Chemical Biology (Nankai University) 

主　　题：drug delivery micelles redox-responsive curcumin polymer-drug conjugate 

摘      要：Redox-responsive polymer-drug conjugate micelles are excellent nanoscale vehicles for self-immolative intracellular drug delivery. To covalently connect the polymer and drug, disulfide-bearing linkers, such as 3,3’-dithiodipropionic acid (DDPA) and 4,4’-dithiodibutyric acid (DDBA), are used. In this paper, we report the influence of linker length on the therapeutic outcome of redox-sensitive conjugate micelles. Curcumin was selected as the model drug and it was conjugated to a multivalent methoxy poly(ethylene glycol)-polylysine copolymer with DDPA or DDBA as the linker. The obtained two polymer-curcumin conjugates were amphiphilic and could self-assemble into micelles that have a hydrodynamic diameter less than 100 nm. The loading of curcumin in both micelles was above 20% (w/w). Irrespective of the linker type, micelle disassembly was observed due to the collapse of the disulfide bond in a reducing environment. However, the rate of curcumin release was much faster with the DDBA linker than with the DDPA linker as the side product was a 5-membered ring with a low ring strain. The linker length-induced variation of curcumin release kinetics caused a significant difference in the intracellular drug concentration and a higher cytotoxicity was witnessed in three model cell lines (HeLa, PC3, and 4T1) for the micelles with a DDBA linker compared to those containing a DDPA linker. As expected, this phenomenon was also observed in HeLa tumor-bearing nude mice in vivo. The current work highlights the significance of linker length in engineering redox-responsive on-demand delivery systems.