Nonemissive Ruthenium Complexes for Near Infrared-II Photodynamic, Photothermal, Sonodynamic, and Sonothermal Therapy Against Drug-Resistant Cancer

Nine nonemissive Ru(II) complexes have been designed for synergistic NIR-II (1064 nm) photodynamic, photothermal, sonodynamic, and sonothermal therapy targeting cisplatin-resistant nonsmall cell lung cancer. Their quantum yields of singlet oxygen and superoxide anions are significantly elevated under low-power NIR-II laser irradiation or ultrasound treatment. The selected complex RY7 completely eradicated drug-resistant lung cancer tumors in all tested mice when treated simultaneously with NIR-II laser and ultrasound at a minimal drug dosage in vivo and was promptly eliminated from the organism. The application of a single-molecule sensitizer to achieve synergistic NIR-II photodynamic/photothermal/sonodynamic/sonothermal therapy may provide important insights into the treatment of deeply located tumors, tackling tumor hypoxia and addressing the complicated pharmacological mechanisms underlying drug resistance. The two-photon absorption quantum chemical calculations presented in this study may also serve as a powerful tool for the rational design and structure–activity relationship studies of two-photon photosensitizers and optical materials.