Self-immolative micellar drug delivery:The linker matters

查看全文 作　　者：Xuan [1]Meng;Min [1]Gao;Jian [1]Deng;Di [1]Lu;Aiping [1]Fan;Dan [2,3]Ding;Deling [2,3]Kong;Zheng [1]Wang;Yanjun [1]Zhao

机构地区：[1]School of Pharmaceutical Science &Technology,Tianjin Key Laboratory for Modem Drug Delivery &High Efficiency and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),Tianjin University,Tianjin 300072,China;[2]State Key Laboratory of Medicinal Chemical Biology (Nankai University),Tianjin 300071,China;[3]Key Laboratory of Bioactive Materials,Ministry of Education,College of Life Sciences and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),Nankai University,Tianjin 300071,China

出　　处：《Nano Research》索引2018年第11卷第12期,共13页

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 add (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. 关键词：DRUG delivery micelles redox-responsive CURCUMIN polymer-drug CONJUGATE

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Self-immolative micellar drug delivery:The linker matters

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