Mutual promotion of oxidative stress amplification and calcium overload by degradable spatially selective self-cascade catalyst for synergistic tumor therapy

Abstract

A safe and degradable space-selective multifunctional nanocatalyst-CMFO reaches self-cascade catalysis to mutually promote oxidative stress amplification and calcium overload for synergistic tumor therapy with MRI guide. • A degradable spatially selective theranostic agent-CMFO was successfully prepared. • The CMFO attenuates tumor hypoxia and depletes glutathione to amplify the oxidative stress. • The generated Ca 2+ and ·OH mutually promote intracellular accumulation and lead enhanced therapeutic effect. • CMFO has high biosafety and can be used as a MR agent. The insufficient H 2 O 2, hypoxia and GSH overexpression in tumor microenvironment led to the strong tolerance of cancer cells to various ROS treatments and seriously restrict their therapeutic effect. Hereby, we fabricated a degradable spatially selective multifunctional nanocatalyst-CMFO to synergistically amplify oxidative stress and overload calcium for tumor treatment. The CMFO was constituted by MnFe 2 O 4 nanoparticles as a protective umbrella to coat CaO 2 , which is stable in normal tissues and leads to specific self-cascade catalytic reaction after accumulation in tumor sites. The nano-CaO 2 releases abundant Ca 2+ and sufficient H 2 O 2 , and Mn/Fe ions released from MnFe 2 O 4 catalyze H 2 O 2 into toxic ·OH. MnFe 2 O 4 and H 2 O 2 can also attenuate tumor hypoxia and deplete intracellular reductant-glutathione (GSH), amplifying the oxidative stress and enhancing ROS-related treatment. More importantly, the generated Ca 2+ and ·OH mutually promote their intracellular accumulation by calcium channels and mitochondria, leading enhanced apoptosis of tumor cells. In addition, CMFO can be used as MR agent to identify tumors and monitor the treatment process. Thus, the as-prepared intelligent biodegradable CMFO provides a novel solution for tumor-specific ROS-related treatment and opens a new door for spatially selective self-cascade synergistic therapy.