Department of Pharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China,
Int J Nanomedicine. 2018 Jul 30;13:4417-4431. doi: 10.2147/IJN.S170035. eCollection 2018.
Iridium (Ir)-based complex is a potential antitumor ingredient, but its poor physicochemical properties such as hydrophobicity and low biocompatibility hamper further application. Liposome provides a potential delivery approach for improving the poor physicochemical property and reducing the side effects of antitumor drug. In this study, we aimed at incorporating Ir ([Ir(ppy)(BTCP)]PF) into liposomes to enhance the biocompatibility and sustained release of Ir for intravenous administration and to elucidate the mechanism in A549 cells.
Ir-loaded PEGylated liposomes (Lipo-Ir) were formulated by thin-film dispersion and ultrasonic method. Morphology, size distribution, and zeta potential of Lipo-Ir were examined by transmission electron microscopy (TEM) and Zetasizer. The released profile and biocompatibility were investigated by dialysis method and hemolysis test, respectively. Additionally, the cytotoxic activity and mechanism of Lipo-Ir and Ir inducing apoptosis in A549 cells were evaluated.
Lipo-Ir can keep sustained release, excellent biocompatibility, and physical stability. The average particle size, polydispersity index, zeta potential, encapsulation efficiency, and drug loading are 112.57±1.15 nm, 0.19±0.02, -10.66±0.61 mV, 94.71%±3.21%, and 4.71%±0.41%, respectively. 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide (MTT) assay show that Lipo-Ir and Ir display high cytotoxicity against selected cancer cells. Furthermore, the apoptotic features of morphology, depolarization of mitochondrial membrane potential, increase in the reactive oxygen species (ROS) levels, and disorder of Ca homeostasis are observed after treating A549 cells with Ir and Lipo-Ir. Besides, Lipo-Ir can arrest the cell growth in G/G phase.
The studies demonstrate that Lipo-Ir can trigger apoptosis in A549 cells via ROS-mediated mitochondrial dysfunctions, and the biocompatible and sustained Lipo-Ir will be a promising drug delivery system.
铱（Ir）基配合物是一种有潜力的抗肿瘤成分，但它的疏水性和低生物相容性等较差的理化性质限制了其进一步应用。脂质体为改善抗肿瘤药物的理化性质差和降低副作用提供了一种潜在的给药途径。本研究旨在将 Ir([Ir(ppy)(BTCP)]PF) 包载入脂质体中，以提高 Ir 的生物相容性和静脉注射时的持续释放，并阐明其在 A549 细胞中的作用机制。
采用薄膜分散法和超声法制备 Ir 载 PEG 化脂质体（Lipo-Ir）。采用透射电子显微镜（TEM）和 Zetasizer 观察 Lipo-Ir 的形态、粒径分布和 Zeta 电位。通过透析法和溶血试验分别考察其释放特性和生物相容性。此外，还评价了 Lipo-Ir 和 Ir 诱导 A549 细胞凋亡的细胞毒性和作用机制。
Lipo-Ir 具有持续释放、良好的生物相容性和物理稳定性。平均粒径、多分散指数、Zeta 电位、包封率和载药量分别为 112.57±1.15nm、0.19±0.02、-10.66±0.61mV、94.71%±3.21%和 4.71%±0.41%。3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐（MTT）法显示，Lipo-Ir 和 Ir 对选定的癌细胞具有高细胞毒性。此外，用 Ir 和 Lipo-Ir 处理 A549 细胞后，观察到形态学的凋亡特征、线粒体膜电位去极化、活性氧（ROS）水平升高和钙稳态紊乱。此外，Lipo-Ir 可将细胞生长阻滞在 G0/G1 期。
本研究表明，Lipo-Ir 通过 ROS 介导的线粒体功能障碍诱导 A549 细胞凋亡，具有生物相容性和持续释放的 Lipo-Ir 将是一种有前途的药物递送系统。
