Enhanced in vitro cytotoxicity and antitumor activity in vivo of iridium(III) complexes liposomes targeting endoplasmic reticulum and mitochondria.

In this paper, two new iridium(III) complexes [Ir(ppy) 2 (CBIP)](PF 6) (ppy = 2-phenylpyridine, CBIP = 2-(4′-chloro-(1,1′-biphenyl))-1 H -imidazo[4,5-f][ 1 , 10 ]phenanthroline) (Ir1) and [Ir(piq) 2 (CBIP)](PF 6) (piq = 1-phenylisoquinoline) (Ir2) were synthesized and characterized. The anticancer activity of the complexes against cancer A549, HepG2, SGC-7901, BEL-7402, HeLa and LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, the complexes exhibit no or low cytotoxic activity toward the selected cancer cells. To increase the anticancer activity, complexes Ir1 and Ir2 were encapsulated into the liposome to form Ir1lipo and Ir2lipo , while Ir1lipo and Ir2lipo show high cytotoxic efficacy against BEL-7402, SGC-7901 and HeLa cells and Ir2lipo displays moderate cytotoxic activity against A549 and HepG2. The anticancer mechanism was explored through wound healing, cell cycle arrest, apoptosis, the change of mitochondrial membrane potential and antitumor activity in vivo. The antitumor in vivo showed that Ir1Lipo (3.9 mg/kg) exhibited significant antitumor activity with an inhibitory rate of 62.16%. Additionally, the expression of B-cell lymphoma-2 family proteins was studies by western blotting analysis. The results demonstrate that Ir1lipo and Ir2lipo induce apoptosis in BEL-7402 cells via endoplasmic reticulum stress-mitochondrial pathway. [Ir(ppy) 2 (CBIP)](PF 6) (ppy = 2-phenylpyridine, Ir1), [Ir(piq) 2 (CBIP)](PF 6) (piq = 1-phenylisoquinoline, CBIP = 2-(4′-chloro-(1,1′-biphenyl))-1 H -imidazo[4,5-f] [1,10]phenanthroline, Ir2), complex-loaded liposomes Ir1lipo and Ir2lipo were synthesized. The anticancer activity in vitro and in vivo of the complexes and their liposomes were evaluated. [Display omitted] • Three iridium(III) complexes and complex-loaded liposomes were synthesized. • The cytotoxicity in vitro and in vivo of the complexes and liposomes was studied. • The apoptosis and cell cycle arrest were performed. • The location of the complexes at the endoplasm reticulum and mitochondria was explored. • The expression of B-cell lymphoma-2 family proteins was assayed. [ABSTRACT FROM AUTHOR]