Mitochondria-Targeting 1H-Imidazo[4,5-f][1,10]phenanthroline-Based Binuclear Ru(II)/Ir(III)/Re(I) Complexes as a Promising Avenue for In Vitro Genotoxicity and In Vivo Tumor Immunotherapy.

Abstract

Bimetallic complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology. However, the effectiveness of existing therapies remains limited in the treatment of triple-negative breast cancer (MDA-MB-231) and human melanoma cancer (A375). In this study, we introduced mitochondrial-targeting imidazophenanthroline-based binuclear Ru(II)/Ir(III)/Re(I) complexes capable of generating ROS, facilitating mitochondrial dysfunction and oxidative DNA damage, and inducing G0/G1 phase cell cycle arrest. Among all these complexes, the naphthalene-substituted imidazophenanthroline-based bisiridium complex (BNS-2) exhibited the best potency against MDA-MB-231 TNBC and A375 cancer cell lines. Eventually, this complex induced the upregulation of BAX and cleaved caspase-3, downregulated BCL-2, triggered the caspase 3/9 pathway for apoptosis, and shifted the death mechanism from necrosis to apoptosis in tumor cells in vivo. This complex significantly reduced tumor volume and protected the mice against significant weight loss without causing liver or kidney toxicity.