Metal–Organic Framework and 5-Fluorouracil Co-Encapsulated Hyaluronic Acid/Carboxymethyl Chitosan Hydrogels for Synergistic Chemotherapy and Enhanced Chemodynamic Therapy

A vitamin K3 (VK3)-loaded metal–organic framework (Cu/ZIF-8/VK3) was synthesized by a one-pot method. After the coencapsulation of Cu/ZIF-8/VK3 and 5-fluorouracil (5-FU) in the hyaluronate acid (HA)/carboxymethyl chitosan (CMCS) hydrogels formed via an amidation reaction, a drug-controlled release system (Cu/ZIF-8/VK3/5-FU/HA/CMCS) was obtained. In the weakly acidic media, the amide bonds in the HA/CMCS hydrogels are prone to be hydrolyzed, resulting in the release of 5-FU and Cu/ZIF-8/VK3; and the Cu/ZIF-8/VK3 is further degraded in the acidic environment, leading to the release of VK3 and Cu2+. The released Cu2+ can be reduced by glutathione (GSH) to Cu+, which can react with intracellular H2O2 to produce cytotoxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). On the other hand, H2O2 can be replenished through the redox cycling of VK3 in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), generating stable ·OH for enhanced CDT. Cytotoxicity assay demonstrates that the developed drug-controlled release system has excellent biocompatibility, which can effectively inhibit the growth of mouse breast tumor cells 4T1 due to the synergistic chemotherapy and enhanced CDT.