One-Step Integration of Tumor Microenvironment-Responsive Calcium and Copper Peroxides Nanocomposite for Enhanced Chemodynamic/Ion-Interference Therapy

Tailored to the specific tumour microenvironment, which involves acidity and the overproduction of hydrogen peroxide, advanced nanotechnology has been introduced to generate the hydroxyl radical (. OH) primarily for tumour chemodynamic therapy (CDT) through the Fenton and Fenton-like reactions. Numerous studies have investigated the enhancement of CDT efficiency, primarily the increase in the amount of . OH generated. Notably, various strategies based on the Fenton reaction have been employed to enhance . OH generation, including nanomaterials selection, modulation of the reaction environment, and external energy fields stimulation, which are discussed systematically in this Minireview. Furthermore, the potential challenges and the methods used to facilitate CDT effectiveness are also presented to support this cutting-edge research area. Show more

Tumor cells metabolize in distinct pathways compared with most normal tissue cells. The resulting tumor microenvironment would provide characteristic physiochemical conditions for selective tumor modalities. Here we introduce a concept of sequential catalytic nanomedicine for efficient tumor therapy by designing and delivering biocompatible nanocatalysts into tumor sites. Natural glucose oxidase (GOD, enzyme catalyst) and ultrasmall Fe3O4 nanoparticles (inorganic nanozyme, Fenton reaction catalyst) have been integrated into the large pore-sized and biodegradable dendritic silica nanoparticles to fabricate the sequential nanocatalyst. GOD in sequential nanocatalyst could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H2O2 for subsequent Fenton-like reaction catalyzed by Fe3O4 nanoparticles in response to mild acidic tumor microenvironment. Highly toxic hydroxyl radicals are generated through these sequential catalytic reactions to trigger the apoptosis and death of tumor cells. The current work manifests a proof of concept of catalytic nanomedicine by approaching selectivity and efficiency concurrently for tumor therapeutics. Show more

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy. Show more