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One of the most promising strategies for the controlled release of therapeutic molecules is stimuli-responsive and biodegradable hydrogels developed from natural polymers. However, current strategies to development stimuli-responsive hydrogels lack precise control over drug release profile and use cytotoxic materials during preparation. To address these issues, multi-stimuli responsive hydrogels derived from hyaluronic acid and diselenide based cross-linker were developed for the controlled release of doxorubicin (DOX). Hydrogels were rapidly formed via an inverse electron demand Diels-Alder click chemistry and encapsulated DOX/indocyanine green (ICG) in their porous networks. The hydrogels showed a rapid release of DOX in acidic (pH 5), reducing (10 mmol DTT), and oxidizing medium (0.5% H

In this work, novel injectable and reduction-responsive hydrogels were successfully prepared via inverse electron demand Diels-Alder reaction between alginate-norbornene and a water-soluble PEG based disulfide cross-linker. The reduction-responsive cross-linker was designed to contain a PEG chain within two disulfide linkages, and two terminal tetrazine groups. The resulting hydrogels possessed high swelling ratios, porous morphology, excellent drug loading efficiency (~92%), and suitable mechanical properties. The drug release experiments demonstrated that the hydrogels released more than 90% of the encapsulated doxorubicin (DOX) in the presence of 10 mM glutathione while a minimal DOX release (25%) was measured in physiological buffer (PBS, pH = 7.4) after 11 d. The cross-linker and hydrogels did not exhibit any apparent cytotoxicity to fibroblast cells. In contrast, DOX-loaded hydrogels induced anti-tumor activity against cancer cells. The injectable and reduction-responsive hydrogels hold great potential as a biomaterial for stimuli responsive drug delivery applications.