Redox-Responsive Polyurethane Nanonetworks with Tunable Cross-linking: A Robust Platform for Cocktail Chemotherapy

We formulated a nanonetwork of an amphiphilic polyurethane integrated with a tertiary amine group on the backbone and a pyridyl disulfide group as a pendant. The disulfide linkages within the nanonetwork undergo reductive cleavage in the intracellular redox environment of cancer cells, enabling sustained and site-specific drug release. The positive surface-charge generation under tumor extracellular matrix-like mildly acidic conditions promotes selective uptake of the nanonetwork by cancer cells while minimizing interaction with normal cells, as shown by flow cytometry analysis. Biological evaluation confirmed selective internalization and potent cytotoxicity in HeLa and MDA-MB-231 cells following treatment with NN@DOX, while normal cells were effectively shielded from off-target toxicity. Furthermore, the dual-drug-loaded nanonetwork (NN@DOX-CPT) exhibited superior therapeutic outcomes, as demonstrated by a significantly lower IC₅₀ (3.98 μg/mL) value compared to single-drug formulations, NN@DOX (IC₅₀ = 9.89 μg/mL), confirming a combined effect. Overall, this polymeric nanonetwork could be a promising system for combination drug-based targeted chemotherapy.