Exploring a novel asymmetric tris-heteroleptic iridium(III) complex as mitochondria-targeted anticancer agents

Organometallic iridium(III) complexes are a highly promising class of metal-based anticancer agents. In this study, three bis-/tris-heteroleptic iridium(III) complexes-[Ir(piq)₂(bpy)]PF₆ (Ir1), [Ir(piq)(btp)(bpy)]PF₆ (Ir2) and [Ir(btp)₂(bpy)]PF₆ (Ir3)-were synthesized and characterized, where piq = 1-phenylisoquinoline, btp = 2-(benzothienyl)pyridine and bpy = 2,2'-bipyridine. Their photophysical properties were studied, and theoretical calculations were conducted to better understand the variations along the series. All complexes exhibited potent cytotoxicity against tumor cells, among which tris-heteroleptic complex Ir2 showed superior activity toward HeLa cells-prompting comprehensive antitumor studies of this complex. Laser confocal assay revealed that Ir2 entered cells via an energy-dependent uptake mechanism while exhibiting specific mitochondrial targeting, as evidenced by a high Pearson's colocalization coefficient (PCC = 0.93). Subsequent biological assays-including apoptosis analysis, cell cycle arrest, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) changes-revealed that complex Ir2 induced HeLa cells apoptosis through mitochondrial dysfunction. The antitumor activity in vivo confirmed that Ir2 could effectively suppressed tumor growth in HeLa xenograft-bearing mice (61.80 % inhibition) without adverse effects on major organs. Overall, complex Ir2 represents a novel asymmetric tris-heteroleptic iridium(III) complex developed for anticancer applications, with results demonstrating its excellent antitumor efficacy, thereby positioning its potential as a new alternative to conventional anticancer agents.