Design of Cyclometalated Iridium(III) Complexes with Tailored Ancillary Ligands for Mitochondria-Targeted Dual Chemo-Phototherapy

In this study, we report a series of cationic, mitochondria-targeted cyclometalated iridium(III) complexes (<b>Ir1-Ir5</b>) engineered for dual chemo- and phototherapeutic applications. Structural modifications of the bipyridyl ancillary ligands with bioactive substituents were systematically examined to evaluate their impact on anticancer activity. Confocal microscopy revealed selective mitochondrial accumulation of all complexes in cancer cells. The complexes exhibited potent chemotherapeutic effects against multiple 2D monolayer cancer cell lines, including lung (A549), breast (MCF7), ovarian (A2780), and cisplatin-resistant ovarian (A2780cisR) cancers, with IC₅₀ values ranging from 1.0 to 4.84 μM. Upon visible-light activation, they demonstrated pronounced phototherapeutic efficacy, achieving nanomolar IC₅₀ values (40-380 nM) and phototoxicity indices (PI) of approximately 7-69. Among them, <b>Ir4</b> showed the highest mitochondrial localization and the strongest phototoxic profile. Mechanistic investigations indicated that <b>Ir4</b> triggers multimodal cell death via mitochondrial membrane potential disruption, ROS generation, NADH oxidation, cell-cycle arrest, and apoptosis and also suppresses cancer cell migration, suggesting antimetastatic potential. Furthermore, <b>Ir4</b> displayed robust light-induced phototherapeutic activity in dense 3D multicellular tumor spheroids (MCTSs), with an IC₅₀ of 0.9 μM, demonstrating effective penetration and therapeutic action in tumor-like environments. Overall, these findings highlight mitochondria-targeted iridium(III) complexes as promising agents for integrated chemo-photodynamic cancer therapy.