Cyclometallated Ir(III) complexes exhibit antitumor activity through angiogenesis inhibition

Targeting angiogenesis remains a pivotal therapeutic approach in cancer treatment, aiming to impede tumor growth and metastasis. In this study, three novel cyclometallated Ir(III) complexes (Ir1, Ir2, and Ir3) were synthesized and systematically assessed for their in vitro cytotoxic effects across a range of cancer cell lines. Mechanistic studies revealed that these complexes are internalized by MCF-7 cells via energy-dependent pathways and predominantly accumulate within lysosomes or the endoplasmic reticulum. Moreover, treatment with Ir1-Ir3 markedly reduced mitochondrial membrane potential, induced significant reactive oxygen species (ROS) generation, and triggered pyroptosis, culminating in the release of pro-inflammatory cytokines. Importantly, all three complexes demonstrated pronounced, dose-dependent antiangiogenic activity in zebrafish embryonic models. In vivo antitumor evaluations further confirmed their potent tumor growth-inhibitory effects, underscoring their dual functionality as both cytotoxic agents and angiogenesis inhibitors.