School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, PR China.
J Inorg Biochem. 2020 Apr;205:111014. doi: 10.1016/j.jinorgbio.2020.111014. Epub 2020 Jan 31.
Three iridium(III) complexes Ir(ppy)(CPIP) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), Ir(ppy)(DCPIP) (Ir-2, DCPIP = 2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and Ir(ppy)(TCPIP) (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 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.
三种铱（III）配合物Ir(ppy)(CPIP)（Ir-1，ppy=2-苯基吡啶，CPIP=2-(4-氯苯基)-1H-咪唑[4,5-f][1,10]菲咯啉）、Ir(ppy)(DCPIP)（Ir-2，DCPIP=2-(3,4-二氯苯基)-1H-咪唑[4,5-f][1,10]菲咯啉）和Ir(ppy)(TCPIP)（Ir-3，TCPIP=2,3,5-三氯苯基)-1H-咪唑[4,5-f][1,10]菲咯啉）被合成并进行了表征。将配合物 Ir-1、Ir-2 和 Ir-3 包封在脂质体中形成 Ir-1-Lipo、Ir-2-Lipo 和 Ir-3-Lipo。通过透射电子显微镜（TEM）和 Zetasizer 检查了脂质体的形态、粒径分布和zeta 电位。通过 3-(4,5-二甲基噻唑-2-基)-2,5-联苯四唑溴盐（MTT）法评估了 Ir-1、Ir-2 和 Ir-3 对选定的癌细胞 A549、HTC-116、HepG2、BEL-7402、Eca-109、B16、HeLa SGC-7901 和正常 NIH3T3 细胞的体外细胞毒性活性。Ir-2 和 Ir-3 对所选癌细胞没有细胞毒性活性，而 Ir-1 对 A549 细胞的细胞生长显示出中等的细胞毒性作用。然而，将 Ir-1、Ir-2 和 Ir-3 包封在脂质体中，细胞毒性活性大大增强。特别是，Ir-1-Lipo 和 Ir-2-Lipo 可以有效地抑制 A549 细胞的细胞生长，IC 值分别为 3.1±0.3 和 1.2±0.4 μM。通过流式细胞术检测细胞凋亡。Ir-1、Ir-2 和 Ir-3 显示出较弱的凋亡作用，而 Ir-1-Lipo、Ir-2-Lipo 和 Ir-3-Lipo 分别诱导 A549 细胞的凋亡率为 55.6%、69.3%和 16.7%。特别是，在体内抗肿瘤活性试验中，Ir-2 诱导的肿瘤生长抑制率为 27.65%，而 Ir-2-Lipo 诱导的肿瘤生长抑制率为 57.45%。显然，与配合物相比，脂质体可以增强体外和体内的抗癌活性。结果表明，包封铱（III）配合物的脂质体通过 ROS 介导的溶酶体-线粒体功能障碍途径诱导 A549 细胞凋亡，并靶向微管。
