Synthesis and in vitro studies of doxorubicin-Cu2+ prodrug and glucose oxidase co-encapsulated oxidized hyaluronic acid/carboxymethyl chitosan hydrogels on breast cancer cell line 4T1.

Breast cancer is one of the most life-threatening malignancies worldwide, and the chemotherapy of breast cancer is often hindered by drug resistance and systemic toxicity. Developing safer and more efficient multi-therapy strategies is therefore urgently needed. Doxorubicin (DOX) is first combined with Cu2+ through coordination bonds, and the resulting DOX-Cu2+ prodrug is then co-encapsulated with glucose oxidase (GOx) in the oxidized hyaluronic acid (OHA)/carboxymethyl chitosan (CMCS) hydrogels cross-linked through the Schiff base reaction. The weakly acidic environment of tumor cells can cause the degradation of the hydrogels and the dissociation of the DOX-Cu2+ complex, resulting in the release of DOX for chemotherapy. The released Cu2+ can be reduced to Cu + by glutathione (GSH), and the Cu+ can participate in the Fenton-like reaction with the overexpressed H2O2 in tumor cells to produce hydroxyl radicals (·OH) for chemodynamic therapy (CDT). During the degradation of the hydrogels, the GOx is also released, which can deplete the glucose in tumor cells for starvation therapy; meanwhile, the H2O2 generated during the GOx-catalyzed oxidation of glucose can in turn participate in the Fenton-like reaction with Cu+ to enhance CDT. The results of cytotoxicity assay indicate that the OHA/CMCS hydrogels have good biocompatibility, while the DOX-Cu2+ and GOx co-encapsulated hydrogels (OHA/CMCS/DOX-Cu2+/GOx) display significant cytotoxicity due to the multi-therapy synergies of chemotherapy, enhanced CDT and starvation therapy.