Cyclometalated
iridium(III) complexes are of significant importance in the field of antitumor
photodynamic therapy (
PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and
PDT effectiveness remains awaited. The influencing factors of two-photon excited
PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline
ligand containing YQ2 was found to be the most potent infrared two-photon excitable
photosensitizer in a 4 × 3 combination library of cyclometalated Ir(III) complexes. YQ2 could enter cells via an energy-dependent and caveolae-mediated pathway, bind specifically to mitochondria, produce 1O2 in response to 808 nm LPL irradiation, activate
caspases, and induce apoptosis. In vitro, YQ2 displayed a remarkable
phototherapy index for both
malignant melanoma (>885) and
non-small-cell lung cancer (>1234) based on these functions and was minimally deleterious to human normal liver and kidney cells. In in vivo antitumor
phototherapy, YQ2 inhibited
tumor growth by an impressive 85% and could be eliminated from the bodies of mice with a half-life as short as 43 h. This study has the potential to contribute significantly to the development of phototherapeutic drugs that are extremely effective in treating large, profoundly located solid
tumors as well as the understanding of the structure-activity relationship of Ir(III)-based PSs in
PDT.