Hydrogen gas can mitigate oxidative stress in many diseases and is regarded to be safe and free of side effects. Inspired by a metalloenzyme in a variety of microorganisms, here, we propose a photoactivated H2 nanogenerator that comprises a fluorinated chitosan (FCS), a chemotherapeutic drug (gemcitabine, GEM), and a catalyst of H2 production ([FeFe]TPP) that can form self-assembled [FeFe]TPP/GEM/FCS nanoparticles (NPs). The [FeFe]TPP/GEM/FCS NPs exhibit excellent transmucosal and tumor cell penetration capacities after intravesical instillation into the bladder and can efficiently produce H2 gas in situ upon 660 nm laser irradiation, which significantly enhances the efficacy of hydrogen chemotherapy of cancer in vitro and in vivo. Moreover, we discover that H2 gas in hydrogen chemotherapy can inhibit mitochondrial function, hinder ATP synthesis, and cause a reduction of the P-gp efflux pump function, which finally attenuates P-gp protein drug transport capacity in cancer cells. This photoactivated H2 evolution in situ to improve the therapeutic efficacy of chemotherapy of bladder cancer may present an effective hydrogen chemotherapy strategy for cancer treatment.
Keywords: bladder cancer; cell-penetrating and transmucosal delivery; hydrogen chemotherapy; mitochondrial function; photoactivated H2 gas.