Abstract
This study explores the therapeutic potential of seven bis-cyclometalated Ir(III) complexes (1-7), derived from the 2,2'-(benzothiazolyl)benzimidazole scaffold, as highly promising next-generation photoactivatable agents for type I and type II-guided photodynamic therapy (PDT) in lung and colorectal cancers. Their high phototoxicity in 2D and 3D cancer cell models, achieving IC(50) values in the nanomolar region, was closely linked to the generation of singlet oxygen and type I reactive oxygen species (ROS) and the photooxidation of NADH, with complex 4 identified as the strongest ROS inducer and the most photocytotoxic complex. Notably, the iridium complexes proved to maintain their phototoxicity in hypoxic conditions. Using 3D spheroids, complex 4 demonstrated deep tissue penetration sought to overcome PDT limitations in solid tumors. Overall, the synthesized complexes showcase high efficacy and favorable pharmacological profiles, positioning them as promising candidates for the ROS-guided photodynamic treatment of cancers, including those located within hypoxic environments.