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Two iridium(III) polypyridyl complexes [Ir(ppy) 2 (HPIP)](PF 6) (Ir-1), [Ir(ppy) 2 (BHPIP)](PF 6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC 50 values range from 5.2 ± 0.8 to 22.3 ± 1.8 μM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase. Two iridium(III) complexes [Ir(ppy) 2 (HPIP)](PF 6) (Ir - 1) and [Ir(ppy) 2 (BHPIP)](PF 6) (Ir - 2) were synthesized and characterized. The complexes Ir-1 and Ir-2 were encapsulated in liposomes Ir-1-Lipo and Ir-2-Lipo. The anticancer activity of the complexes and liposomes was investigated by apoptosis, comet assay, ROS, mitochondrial membrane potential, release of cytochrome c , tubules and Western blot analysis and in vivo antitumor activity. Image 1 • Two iridium(III) complexes Ir-1 and Ir-2 and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized. • The cytotoxicity in vitro or in vivo of the complexes and liposomes was investigated. • The apoptosis and cell cycle distribution were assayed by flow cytometry. • ROS and mitochondrial membrane potential were studied under fluorescence microscope. • The expression of Bcl-2 family proteins was assayed by western blot analysis. [ABSTRACT FROM AUTHOR]

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy) 2 (adppz)](PF 6) (Ir-1), [Ir(bzq) 2 (addpz)](PF 6) (Ir-2) and [Ir(piq) 2 (adppz)](PF 6) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1 , Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC 50 values are 1.8 ± 0.4, 1.6 ± 0.3 and 0.8 ± 0.1 μM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca2+ levels, mitochondrial membrane potential collapse and massive release of cytochrome c , it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs. Three new iridium(III) complexes were synthesized and characterized. The cytotoxicity in vitro and in vivo was investigated. The complexes show high anticancer activity in vitro and in vivo. Image 1 • The iridium(III) complexes were synthesized and characterized. • The cytotoxicity in vitro was studied by MTT method. • The apoptosis, cell cycle arrest and intracellular ROS levels were assayed. • The effect of the complex on the tumor growth was evaluated. [ABSTRACT FROM AUTHOR]

Three iridium(III) complexes [Ir(ppy) 2 (CPIP)](PF 6) (Ir-1 , ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy) 2 (DCPIP)](PF 6) (Ir-2 , DCPIP = 2-(3,4-dichlorophenyl)-1 H -imidazo[4,5- f ][1,10]phenanthroline) and [Ir(ppy) 2 (TCPIP)](PF 6) (Ir-3 , TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The complexes Ir-1 , Ir-2 and Ir-3 were encapsulated in liposomes to form Ir-1-Lipo , Ir-2-Lipo and Ir-3-Lipo. Morphology, size distribution, and zeta potential of liposomes were examined by transmission electron microscopy (TEM) and Zetasizer. The cytotoxic activity in vitro of Ir-1 , Ir-2 and Ir-3 against cancer A549, HTC-116, HepG2, BEL-7402, Eca-109, B16, HeLa SGC-7901 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir-2 and Ir-3 show no cytotoxic activity against the selected cancer cells, and Ir-1 displays moderate cytotoxic effect on the cell growth in A549 cells. However, Ir-1 , Ir-2 and Ir-3 were encapsulated in liposomes, the cytotoxic activity was greatly enhanced. In particular, Ir-1-Lipo and Ir-2-Lipo can effectively inhibit the cell growth in A549 cells with a low IC 50 value of 3.1 ± 0.3 and 1.2 ± 0.4 μM. The apoptosis was assayed by flow cytometry. Ir-1 , Ir-2 and Ir-3 reveal weak apoptotic effect, whereas Ir-1-Lipo , Ir-2-Lipo and Ir-3-Lipo induce an apoptotic percentage of 55.6%, 69.3% and 16.7% in A549 cells, respectively. Specially, in the assay of antitumor activity in vivo, the inhibiting percentage of tumor growth induced by Ir-2 is 27.65%, while inhibiting percentage of tumor growth caused by Ir-2-Lipo is 57.45%. Obviously, the liposomes can enhance anticancer activity in vitro and in vivo compared with the complexes. The results show that the iridium(III) complexes encapsulated liposomes induce apoptosis in A549 cells through ROS-mediated lysosome-mitochondria dysfunction pathway and target the microtubules. Iridium(III) complexes [Ir(ppy) 2 (CPIP)](PF 6) (Ir - 1 , ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1 H -imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy) 2 (DCPIP)](PF 6) (Ir - 2 , DCPIP = 2-(3,4-dichlorophenyl)-1 H -imidazo[4,5- f ][1,10]phenanthroline) and [Ir(ppy) 2 (TCPIP)](PF 6) (Ir - 3 , TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. Ir-1 , Ir-2 and Ir-3 were encapsulated in liposomes Ir-1-Lipo , Ir-2-Lipo and Ir-3-Lipo. The anticancer activity of them was investigated in vitro and in vivo. Unlabelled Image • Complexes Ir-1, Ir-2, Ir-3 and their liposomes were synthesized and characterized. • The cytotoxicity in vitro was studied by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. • Colonies, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential were investigated. • The effect of liposomes Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo on microtubules was explored. • The antitumor in vivo of Ir-2-Lipo was studied. [ABSTRACT FROM AUTHOR]