Self-targeted nanosystem for enhanced chemodynamic cancer therapy

Chemodynamic therapy (CDT) could have a significant potential for advancing cancer treatment <i>via</i> the utilization of Fenton and Fenton-like reactions, which produce toxic reactive species. Nonetheless, the efficacy of CDT is constrained by the limited availability of catalyst ions capable of decomposing pre-existing intracellular H₂O₂ and generating reactive oxygen species (ROS) necessary to achieve a therapeutic response. To address these limitations, a tailored strategy has been developed to enhance the efficacy of Fenton-like reactions to eradicate selectively cancer cells. This innovative approach involves the utilization of dual metal cations (Zn²⁺, Fe²⁺) within zinc nitroprusside (ZnNP) material. Remarkably, this method takes advantage of the acidic conditions prevalent in tumors, thus eliminating the need for external stimuli. Through these advancements, the tailored approach exhibits the potential to specifically target and eliminate cancer cells, overcoming the mentioned limitations. A simple mixing technique was utilized to synthesize ZnNP, which was structurally and morphologically characterized. Furthermore, extensive <i>in vitro</i> investigations were conducted to assess its anti-tumoral mechanism of action. ZnNP exhibits a remarkable capability to increase intracellular H₂O₂ within cells. This process leads to the generation of various reactive species, including hydroxyl (˙OH) and superoxide (O₂˙^-) radicals, and peroxynitrite (ONOO^-), which act as apoptotic inducers specifically targeting cancer cells. Cellular uptake studies have shown that ZnNP enters the lysosomes, evades degradation, and takes advantage of their acidic pH environment to significantly increase the production of ROS. These findings are further supported by the activation of multiple oxidative genes. Furthermore, the biocompatibility of ZnNP has been demonstrated in <i>ex vivo</i> models using healthy liver cells. Notably, ZnNP exhibited therapeutic effectiveness in high-grade serous ovarian cancer (HGSOC) patient-derived tumor organoids (PDTO), further confirming its potential as a therapeutic agent. The present study highlights the therapeutic potential of ZnNP as a generator of multiple ROS <i>via</i> a Fenton-like reaction. This research offers a promising therapeutic approach for CDT application in combatting HGSOC, a highly aggressive and life-threatening cancer.