Injectable and biocompatible alginate-derived porous hydrogels cross-linked by IEDDA click chemistry for reduction-responsive drug release application.

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.