Dinuclear Dicationic Iridium Complexes for Highly Synergistic Photodynamic and Photothermal Therapy to Chemoresistant Cancer

A series of dinuclear Ir(III) complexes have been constructed for enhanced photodynamic and photothermal therapy (PDT and PTT) for cisplatin-resistant non-small-cell lung cancer. They enter cells via caveolar endocytosis, target mitochondria but not nuclear, generate both singlet oxygen and superoxide anion, and release heat when exposed to infrared (IR) irradiation, thus inducing reactive oxygen species (ROS)-associated cell disruption and thermal ablation. The IR-generated ROS can further activate caspases, triggering apoptosis. Additionally, the ROS deplete intracellular glutathione, lead to lipid peroxidation, and induce ferroptosis. The selected dinuclear Ir(III) complex Ir4 can completely eradicate cisplatin-resistant non-small-cell lung tumor in 75% of the phototreated mice with an inhibition rate of tumor growth above 96%. They have an extremely low toxicity to normal liver and kidney cells. After therapy, metal was not detected in the collected organs of mice except the tumor. A synergistic therapy consisting of potent IR-driven PDT and mild PTT accomplished by single-molecule dinuclear Ir(III) complexes is highly significant for the safe and effective PDT of large, deep-seated tumors as well as for overcoming the complicated drug resistance mechanisms of cancer.