Glutathione-Responsive\nNanoplatforms Based on Coordination\nbetween Fe<sup>3+</sup> and Apigenin for Synergistic Chemo/Chemodynamic\nTherapy

The oxygen consumption during chemodynamic therapy (CDT)\ncan lead\nto severe cellular hypoxia, resulting in an increase in the hypoxia\ninducible factor-1α (HIF-1α) level, which hinders the\neffectiveness of CDT and induces tumor metastasis. Here, we propose\na strategy of synergistic therapy between CDT and the HIF-1α\ninhibitor to avoid the limitations of CDT and reduce the risk of metastasis.\nHerein, based on the coordination between Fe<sup>3+</sup> and apigenin\n(API, HIF-1α inhibitor), we constructed a hyaluronic acid (HA)-modified\nAPI-Fe nanoparticles (AF@HA NPs) for synergetic chemotherapy and glutathione\n(GSH)-activated self-enhancing CDT. AF@HA NPs have high drug loading\ncapacity, stability, and biocompatibility. Furthermore, the overexpressed\nGSH in cancer cells can reduce Fe<sup>3+</sup> to Fe<sup>2+</sup>,\nweakened the coordination between API and Fe, and promoted the release\nof API for chemotherapy. Fe<sup>2+</sup> could react with endogenous\nH<sub>2</sub>O<sub>2</sub> to generate hydroxyl groups for CDT. In\naddition, the released API could inhibit the expression of HIF-1α\nand increase the sensitivity of cells to reactive oxygen species (ROS),\nthereby achieving a synergistic effect between self-enhancing CDT\nand chemotherapy. The results of in vitro and in vivo experiments\nindicated that AF@HA NPs could effectively inhibit tumor growth and\nsuppress the lung metastasis of tumor cells.