Research Article


2018, 11(12): 6177–6189


Self-immolative micellar drug delivery: The linker matters

Xuan Meng1,§, Min Gao1,§, Jian Deng1, Di Lu1, Aiping Fan1, Dan Ding2,3, Deling Kong2,3, Zheng Wang1, and Yanjun Zhao1 (*)

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1 School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern 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
§ Xuan Meng and Min Gao contributed equally to this work.

Keywords: drug delivery, micelles, redox-responsive, curcumin, polymer-drug conjugate
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ABSTRACT 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.
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Self-immolative micellar drug delivery: The linker matters. Nano Res. 2018, 11(12): 6177–6189

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