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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氧化还原反应性聚合物-药物缀合物胶束是用于自消灭细胞内药物递送的出色纳米级载体。为了共价连接聚合物和药物，使用了带有二硫键的接头，例如3,3'-二硫代二丙酸（DDPA）和4,4'-二硫代二丁酸（DDBA）。在本文中，我们报告了接头长度对氧化还原敏感性共轭胶束治疗结果的影响。选择姜黄素作为模型药物，并将其与以DDPA或DDBA为连接基的多价甲氧基聚（乙二醇）-聚赖氨酸共聚物缀合。所获得的两种聚合物-姜黄素结合物是两亲性的，并且可以自组装成具有小于100nm的流体动力学直径的胶束。两个胶束中姜黄素的含量均高于20％（w / w）。不论链接器类型如何，由于在还原环境中二硫键的破坏，观察到了胶束分解。然而，由于副产物为具有低环应变的5元环，因此DDBA接头的姜黄素释放速率比DDPA接头的快得多。接头长度诱导的姜黄素释放动力学变化引起细胞内药物浓度的显着差异，并且在具有DDBA接头的胶束的三种模型细胞系（HeLa，PC3和4T1）中，与含有ABA的胶束相比，见证了更高的细胞毒性。 DDPA链接器。不出所料，这种现象在带有HeLa荷瘤的裸鼠中也观察到 DDBA接头的姜黄素释放速率比DDPA接头快得多，因为副产物是具有低环应变的5元环。接头长度诱导的姜黄素释放动力学变化引起细胞内药物浓度的显着差异，并且在具有DDBA接头的胶束的三种模型细胞系（HeLa，PC3和4T1）中，与含有ABA的胶束相比，见证了更高的细胞毒性。 DDPA链接器。不出所料，这种现象在带有HeLa荷瘤的裸鼠中也观察到 DDBA接头的姜黄素释放速率比DDPA接头快得多，因为副产物是具有低环应变的5元环。接头长度诱导的姜黄素释放动力学变化引起细胞内药物浓度的显着差异，并且在具有DDBA接头的胶束的三种模型细胞系（HeLa，PC3和4T1）中，与含有ABA的胶束相比，见证了更高的细胞毒性。 DDPA链接器。不出所料，这种现象在带有HeLa荷瘤的裸鼠中也观察到 和4T1）中含有DDBA接头的胶束与含有DDPA接头的胶束相比。不出所料，这种现象在带有HeLa荷瘤的裸鼠中也观察到 和4T1）中含有DDBA接头的胶束与含有DDPA接头的胶束相比。不出所料，在携带HeLa肿瘤的裸鼠中也观察到这种现象体内。当前的工作凸显了接头长度在工程氧化还原响应式按需递送系统中的重要性。

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