@article{Meng2018, 
author = {Xuan Meng and Min Gao and Jian Deng and Di Lu and Aiping Fan and Dan Ding and Deling Kong and Zheng Wang and Yanjun Zhao},
title = {Self-immolative micellar drug delivery: The linker matters},
year = {2018},
journal = {Nano Research},
volume = {11},
number = {12},
pages = {6177-6189},
keywords = {drug delivery, micelles, redox-responsive, curcumin, polymer-drug conjugate},
url = {https://www.sciopen.com/article/10.1007/s12274-018-2134-5},
doi = {10.1007/s12274-018-2134-5},
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.}
}