Glutathione-integrated waterborne polyurethanes: aqueous dispersible, redox-responsive biomaterials for cancer drug delivery

• Design of redox-responsive glutathione extended water dispersible WPUs. • Stable WPU membranes with high hydrophilicity and hydrolytic resistance. • Sustained PTX release and responsive release in reductive mimicking conditions. • Enhanced cytotoxicity in HCT-116 cells under reductive environments. • WPUs hold promise for localized cancer therapies with reduced side effects. Waterborne polyurethanes (WPUs) are increasingly recognized for their eco-friendly characteristics and mechanical versatility, offering a sustainable alternative to solvent-based polyurethanes. In this study, redox-responsive glutathione-extended WPUs were developed to enable targeted drug release in the reductive tumour microenvironment. Three WPUs with increasing hydrophilic character were synthesized using a PCL-PEG-PCL triblock copolymer, isophorone diisocyanate and 2,2-bis(hydroxymethyl)propionic acid (DMPA) as an emulsifier, allowing efficient water dispersion of hydrophobic polyurethane segments. A purification process was developed to replace triethylammonium counterions with sodium ions, resulting in a dried polymer easily redispersible in water through autoclaving. Membranes produced from WPU dispersions demonstrated excellent hydrolytic stability and high hydrophilicity. Effective paclitaxel (PTX) loading (40 μg/mg) was achieved during autoclaving and controlled drug release was observed, with increased release rates under reductive conditions. Under homeostatic conditions, less than 20 % of the loaded PTX was released over 16 days, while in a reductive tumour-like environment, the release rate increased to 40 %, indicating strong redox responsiveness. Enhanced cytotoxicity was also observed in HCT-116 cells under simulated reductive conditions. This redox-triggered drug release, responsive to high glutathione levels of tumours, highlights the potential of WPUs for localized cancer therapies. These biomaterials offer a promising platform for developing injectable or implantable WPU-based systems for peritumoral or intratumoral delivery of anticancer drugs, reducing off-target effects and improving treatment efficacy.