Cyclometalated iridium(III) tetrazine complexes for mitochondria-targeted two-photon photodynamic therapy

The fast-moving field of photodynamic therapy (PDT) has provided fresh opportunities to expand the potential of metallodrugs to combat cancers in a light-controlled manner. As such, in the present study, a series of cyclometalated Ir(III) complexes modified with a tetrazine functional group (namely, Ir-ppy-Tz, Ir-pbt-Tz, and Ir-dfppy-Tz) are developed as potential two-photon photodynamic anticancer agents. These complexes target mitochondria but exhibit low toxicity towards HLF primary lung fibroblast normal cells in the dark. When receiving a low-dose one- or two-photon PDT, they become highly potent towards A549 lung cancer cells (with IC₅₀ values ranging from 24.0 nM to 96.0 nM) through the generation of reactive oxygen species (ROS) to induce mitochondrial damage and subsequent apoptosis. Our results indicated that the incorporation of tetrazine with cyclometalated Ir(III) matrices would increase the singlet oxygen (¹O₂) quantum yield (Φ_Δ) and, meanwhile, enable a type I PDT mechanism. Ir-pbt-Tz, with the largest two-photon absorption (TPA) cross-section (σ₂ = 102 GM), shows great promise in serving as a two-photon PDT agent for phototherapy.