Cyclodextrin-grafted thermo/redox dual-responsive polymer mediated by disulfide bridges for regulated drug delivery

Tumor cells usually highly expressed reducing glutathione that can break out disulfide bond. In this article, a novel cyclodextrin-containing thermo/redox dual-responsive polymer, PNIPAM-SS-β-CD, was synthesized by copolymerization between monomers of N-isopropylacrylamide (NIPAM) and mono-methacrylated β-cyclodextrin mediated by disulfide bond (MA-SS-β-CD). The dual- responsive polymer has a weight-average molecular weight (Mw) of 53.75 kDa with 45.5 wt% β-CD content, and the polymerization degree ratio of the two structural units form NIPAM and MA-SS-β-CD in the polymer is about 9.26. The polymer can dissolve in water to form hydrogel with a regulating phase transition temperature from 33 to 36 °C. Cytotoxicity assays and hemolysis tests respectively demonstrated over 95% cell viability and no significant hemolytic activity, indicating its superior biocompatibility. Curcumin was used as a model to evaluate drug loading and in vitro release behavior of the thermo/redox dual-responsive polymer. It was revealed that the copolymer (PNIPAM-SS-β-CD) shows a 5.5 folds higher loaded amount and a slower drug release over 24 h than that of poly(N-isopropylacrylamide) (PNIPAM). Notably, the polymer exhibited rapid drug release through disulfide bond cleavage in response to reduced glutathione (GSH, 3 mM), highlighting its potential for targeted cancer therapy.

肿瘤细胞通常高表达可断裂二硫键的还原性谷胱甘肽（reducing glutathione）。本文中，研究人员通过二硫键介导的N-异丙基丙烯酰胺（N-isopropylacrylamide, NIPAM）与经二硫键修饰的单甲基丙烯酸酯化β-环糊精（MA-SS-β-CD）两种单体的共聚反应，合成了一种新型含环糊精的热/氧化还原双响应聚合物PNIPAM-SS-β-CD。该双响应聚合物的重均分子量（weight-average molecular weight, Mw）为53.75 kDa，β-环糊精含量为45.5 wt%，聚合物中NIPAM与MA-SS-β-CD两种结构单元的聚合度之比约为9.26。该聚合物可溶于水形成水凝胶，其可调相转变温度范围为33至36 ℃。细胞毒性实验与溶血试验结果分别显示，该聚合物的细胞存活率超过95%且无显著溶血活性，表明其具备优异的生物相容性。以姜黄素为模型药物，评估该热/氧化还原双响应聚合物的载药性能与体外释放行为。研究结果表明，与均聚物聚(N-异丙基丙烯酰胺)（poly(N-isopropylacrylamide), PNIPAM）相比，该共聚物（PNIPAM-SS-β-CD）的载药量提升5.5倍，且24小时内的药物释放更为缓慢。值得注意的是，该聚合物可响应3 mM还原型谷胱甘肽（reduced glutathione, GSH），通过二硫键断裂实现快速药物释放，凸显了其在肿瘤靶向治疗中的应用潜力。