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.