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

ABSTRACT

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 H2O2 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 Cu2+, DOX and Cur. Cu2+ can deplete GSH while also being reduced to Cu+; DOX can induce apoptosis and simultaneously boost H2O2 production. Moreover, Cur enhanced the expression of intracellular heme oxygenase-1 (HO-1), for decomposing heme and releasing Fe2+, which further combined with Cu+ to catalyze H2O2 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.