Mitochondria-Targeted Iridium(III) Complexes Entrapped in Liposomes Induce Cell Death through Ferroptosis

Abstract The anticancer efficacy of iridium(III) complexes has been extensively studied. A new ligand TFMPIP (2-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four iridium(III) complexes [Ir(C−N)2(TFMPIP)]PF6 (C−N = ppy: 13a, bzq: 13b, piq: 13c, and dfppy: 13d) were synthesized and characterized. The complexes show moderate or low cytotoxicity against LA795, HCT116, and Huh7 cells, while their liposome formulations 13a@lipo, 13b@lipo, 13c@lipo, and 13d@lipo significantly enhanced the antiproliferative activity against LA795 cells. Mechanistic investigations revealed that 13a@lipo, 13b@lipo, 13c@lipo, and 13d@lipo accumulated in mitochondria and induced pronounced mitochondrial dysfunction. Subsequent experiments confirmed that 13a@lipo, 13b@lipo, 13c@lipo, and 13d@lipo triggered apoptosis, suppressed the PI3K/AKT/mTOR signaling pathway, and induced ferroptosis. In vivo antitumor activity showed that 13c@lipo significantly inhibited tumor growth in the LA795 tumor-bearing model with a high inhibitory rate of 82.72%. Collectively, these findings identify 13c@lipo as a promising liposomal Ir(III)-based candidate for lung adenocarcinoma therapy.