Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2+

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+, but also generate an acidic microenvironment to activate a MOF-Fe2+-based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2O2), which can be consequently converted to highly cytotoxic hydroxyl radicals (center dot OH) via MOF-Fe2+, leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.