Gelatin-based NIR and reduction-responsive injectable hydrogels cross-linked through IEDDA click chemistry for drug delivery application

NIR and reduction-responsive gelatin hydrogels were designed for anti-tumor drug delivery application. Gelatin was functionalized with norbornene (Gel-Nb), followed by covalently cross-linking with a tetrazine (Tz)-based cross-linker (DSe-DPEG-DTz) possessing a redox-cleavable diselenide moiety. The resulting hydrogels were highly porous thanks to the N2 gas produced during the inverse electron demand Diels Alder ‘‘click reaction’’ between Nb and Tz. The hydrogels exhibited enhanced drug loading efficiency (≈ 94%) and excellent swelling ratios. The hydrogel prepared from the Nb:Tz mol. ratio of 10:10 (GHG-C) showed a storage modulus of 1100 Pa with an elastic rheological property. The doxorubicin (DOX)-loaded hydrogels (AR1) released minimal amounts (26%) of DOX at a physiological condition (PBS, pH 7.4). On the contrary, a fast release of DOX was observed in a reducing environment, where > 95% of DOX was released from AR3 after 48 h. The DOX and indocyanine green (ICG) co-loaded hydrogels (AR6) showed a burst release of DOX (>60% after 12 h) upon NIR irradiation, followed by a sustained release of the drug. The combined stimuli of GSH and NIR showed ≈ 85% in half of the total time. Gel-Nb, the cross-linker, and GHG-C were essentially non-toxic to the tested cell lines. Furthermore, AR3 and AR6 restricted the metabolic activities of BT-20 cells after treatment with GSH and NIR irradiation, respectively.