Copper-based metal-organic framework co-loaded doxorubicin and curcumin for anti-cancer with synergistic apoptosis and ferroptosis therapy.

The combination of chemotherapy and ferroptosis therapy can greatly improve the efficiency of tumor treatment. However, ferroptosis-based therapy is limited by the unsatisfactory Fenton activity and insufficient HO supply in tumor cells. In this work, a nano-drug delivery system Cur@DOX@MOF-199 NPs was constructed to combine ferroptosis and apoptosis by loading curcumin (Cur) and doxorubicin (DOX) based on the copper-based organic framework MOF-199. Cur@DOX@MOF-199 NPs decompose quickly by glutathione (GSH), releasing Cu, DOX and Cur. Cu can deplete GSH while also being reduced to Cu; DOX can induce apoptosis and simultaneously boost HO production. Moreover, Cur enhanced the expression of intracellular heme oxygenase-1 (HO-1), for decomposing heme and releasing Fe, which further combined with Cu to catalyze HO for hydroxyl radical (OH) generation, leading to the accumulation of lipid peroxide and ferroptosis. As a result, Cur@DOX@MOF-199 NPs exhibited significantly enhanced antitumor efficacy in MCF-7 tumor-bearing mouse model, suggesting this nano formulation is an excellent synergetic pathway for apoptosis and ferroptosis.