Injectable redox-responsive glutathione-polyurethane/hyaluronic acid hybrid hydrogel for controlled chemotherapy in patient-derived pancreatic cancer organoids

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The synthesis and characterization of a redox-responsive waterborne polyurethane (WPU-GSH) designed for the development of injectable, stimuli-sensitive hybrid hydrogels for localized drug delivery is here reported. WPU-GSH was obtained via reductive depolymerization of oxidized glutathione-extended polyurethane (WPU-GSSG), resulting in an increase in free thiol content from 1.13 to 95 μmol/g and a reduction in molecular weight (from 208.5 to 27.7 kDa). Upon oxidation, thiol groups progressively formed disulfides with a corresponding molecular weight increase to 60 kDa. Hybrid hydrogels were formed by thiol-ene Michael addition between WPU-GSH and vinyl-functionalized hyaluronic acid (HA-DV), yielding injectable systems with tunable gelation times (15–22 min) and viscoelastic properties (G′ up to 600 Pa). Thiolated doxorubicin (DOX-SH) was tethered into the hydrogel at concentrations of 1.06–1.26 mg/mL. Drug release was sustained at pH 7.4 (<20 % over 28 days), reaching 65 % cumulative release under combined acidic and reductive stimuli. In patient-derived pancreatic cancer organoids (PDOs), DOX-loaded hydrogels induced a >97 % reduction in viability within 6 days. • Hydrogels integrate robustness of GSH-waterborne PU with biological potential of HA. • A precise control over hydrogel properties was obtained, enabling injectability. • The design assured sustained DOX release and sharp redox/pH responsiveness. • 3D pancreatic adenocarcinoma organoids validated drug diffusion, and cytotoxicity.