Synthesis of redox-responsive polyurethane nanocapsules for small-molecule delivery and antitumor evaluation on human leukemia K562 cells.

High concentrations of glutathione (GSH) in the tumor microenvironment (TME) represent a promising target for the development of polyurethane (PU)-based redox-responsive drug delivery systems. A series of 3-indolopyrazole acetamide derivatives were designed and synthesized in this study. The anti-proliferative activities of these compounds were evaluated in tumor cell lines, and the small molecule S11 (IC50 = 2.64 μM) was identified as a potent inhibitor of human chronic myeloid leukemia K562 cells. To overcome the challenges of poor solubility and limited stability associated with the hydrophobic small molecule S11, polyurethane nanocapsules containing disulfide bonds (S-S) were innovatively synthesized. Subsequently, drug-loaded polyurethane nanocapsules (S11-1) were synthesized via interfacial polymerization. In vitro experimental results indicated that these nanocapsules exhibit enhanced drug release performance compared to free S11, with a GSH-responsive release mechanism. Furthermore, S11-1 effectively promotes K562 cell apoptosis, elevates intracellular Reactive Oxygen Species (ROS) levels, and induces mitochondrial membrane potential depolarization (MMP). Overall, S11-1 demonstrates considerable potential in enhancing drug delivery efficiency, improving targeting precision, and modulating biological activity.