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 (M_w) 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 <i>in vitro</i> 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.