Dinuclear Ru(II) Complexes for Synergetic Photodynamic, Photothermal, and Sonodynamic Therapy against Cisplatin-Resistant Cancer

A new series of dinuclear Ru(II) complexes with a novel bridging ligand were developed for the treatment of cisplatin-resistant non-small-cell lung cancer via a synergistic photodynamic, photothermal, and sonodynamic therapy mechanism. Comprehensive experimental and theoretical studies investigated their photophysical and photochemical properties along with the influence of ancillary ligands. The complexes exhibit significant two-photon absorption at the IR region, facilitating ROS generation through both type I and II mechanisms under IR laser and ultrasound exposure. They effectively target mitochondria and nuclei, regulating DNA-related mechanisms, including the inhibition of DNA topoisomerase and RNA polymerase while promoting photoactivated apoptosis and ferroptosis. The high synergy effect between IR and ultrasound was attributed to the rise in oxygen availability via ultrasound-induced cavitation and a thermal-induced increase in vascular permeability and oxygen partial pressure. In vivo experiments confirmed that the combination of IR and ultrasound yielded superior therapeutic outcomes compared with single-modality treatments. The tested complex exhibited excellent safety with rapid in vivo clearance and low toxicity to normal cells. These findings suggest that IR-activated metal complexes can significantly advance integrated diagnostic and therapeutic approaches, overcoming challenges such as drug resistance and hypoxic environments in deep tumors.