Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Department of pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Nanomedicine. 2019 Feb;16:236-249. doi: 10.1016/j.nano.2018.12.014. Epub 2019 Jan 9.
Efficient delivery of antioxidant drugs into mitochondria of ischemic cardiomyocytes where reactive oxygen species largely induced is a major challenge for precise treatment of myocardial ischemia-reperfusion injury. Herein, we report a smart dual-shell polymeric nanoparticle, MCTD-NPs, which utilizes multistage continuous targeted strategy to deliver reactive oxygen species scavenger specifically to mitochondria of ischemic cardiomyocytes upon systemic administration. In vitro experiments indicated that the intracellular uptake of MCTD-NPs was specifically enhanced in hypoxia reoxygenation injured H9c2 cells. MCTD-NPs selectively delivered resveratrol to mitochondria of hypoxia reoxygenation injured H9c2 cells. In addition, MCTD-NPs increased the viability of H/R injured H9c2 cell through eliminating mitochondrial ROS, decreasing mPTP opening and blocking mitochondria-dependent apoptotic pathway. In vivo experiments revealed that MCTD-NPs increased the distribution of resveratrol in the ischemic myocardium and subsequently reduced infarct size in MI/RI rats. These results demonstrated a novel platform for specific delivery of antioxidant to mitochondria to treat MI/RI.
高效递送至缺血性心肌细胞的线粒体中，而活性氧物质在很大程度上诱导了这种递送至缺血性心肌细胞的线粒体中，是精确治疗心肌缺血再灌注损伤的主要挑战。在此，我们报告了一种智能双壳聚合物纳米颗粒 MCTD-NPs，它利用多阶段连续靶向策略，在系统给药后将活性氧清除剂特异性递送至缺血性心肌细胞的线粒体。体外实验表明，MCTD-NPs 在缺氧复氧损伤的 H9c2 细胞中的细胞内摄取特异性增强。MCTD-NPs 选择性地将白藜芦醇递送至缺氧复氧损伤的 H9c2 细胞的线粒体。此外，MCTD-NPs 通过消除线粒体 ROS、减少 mPTP 开放和阻断线粒体依赖性凋亡途径，增加 H/R 损伤的 H9c2 细胞的活力。体内实验表明，MCTD-NPs 增加了缺血心肌中白藜芦醇的分布，随后减少了 MI/RI 大鼠的梗死面积。这些结果证明了一种将抗氧化剂特异性递送至线粒体以治疗 MI/RI 的新平台。
