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Self-immolative micellar drug delivery: The linker matters

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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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Author notes

  1. Xuan Meng and Min Gao contributed equally to this work.

Authors and Affiliations

  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

    Xuan Meng, Min Gao, Jian Deng, Di Lu, Aiping Fan, Zheng Wang & Yanjun Zhao

  2. State Key Laboratory of Medicinal Chemical Biology (Nankai University), Tianjin, 300071, China

    Dan Ding & Deling Kong

  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

    Dan Ding & Deling Kong

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  1. Xuan Meng
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  2. Min Gao
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  4. Di Lu
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  5. Aiping Fan
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  8. Zheng Wang
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  9. Yanjun Zhao
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Correspondence to Yanjun Zhao.

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Meng, X., Gao, M., Deng, J. et al. Self-immolative micellar drug delivery: The linker matters. Nano Res. 11, 6177–6189 (2018). https://doi.org/10.1007/s12274-018-2134-5

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  • DOI: https://doi.org/10.1007/s12274-018-2134-5

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