Photocatalytic Anticancer Activity of Cyclometalated Ir(III) Complexes: A Mechanistic Insight

Three novel cyclometalated Ir(III) complexes, Ir1-Ir3, were synthesized and thoroughly characterized. These complexes exhibited absorption in the 350-480 nm range, making them suitable candidates for visible-light-mediated photocatalytic cancer therapy. Under visible-light exposure in a DMSO:PBS (1:99 v/v) solvent system, all three photocatalysts demonstrated high efficiency in facilitating NADH oxidation, attaining turnover frequencies (TOFs) in the range of 499-698 h⁻1, exceeding the performance of most of the previously reported Ir(III)-based photocatalysts. Mechanistic studies verified the involvement of type I and type II pathways for ROS generation. Cytotoxicity studies highlighted significant photocytotoxic effects of Ir1-Ir3 in human lung adenocarcinoma cells (A549), with Ir3 emerging as the most potent under light exposure. Additionally, the negligible dark and light cytotoxicity of Ir3 against human embryonic kidney cells (HEK-293) demonstrated the safety profile of Ir3. Furthermore, the mechanistic studies in A549 cells revealed that Ir3 promoted mitochondrial membrane depolarization and activated caspase-3/7-dependent apoptotic pathways through light-triggered ROS generation and NADH oxidation. These findings highlight Ir3 as a potent dual-action cancer phototherapeutic, capable of synergistically inducing type-I and type-II anticancer activity, and efficient NADH photo-oxidation. This work presents a promising platform for developing multifunctional photocatalytic agents in cancer therapy.