负载黄芪甲苷的心脏—线粒体双靶向递药纳米胶束改善急性心肌梗死后心脏损伤

Astragaloside Ⅳ-loaded heart-mitochondria dual-targeted nanomicelles improved heart injury after acute myocardial infarction

急性心肌梗死(Acute Myocardial Infarction,AMI)因其高患病率和致死率严重威胁人类健康,尽管药物、介入治疗和外科手术极大程度地降低了AMI的死亡率,但AMI后仍存在持续的心肌损伤。黄芪甲苷(Astragaloside Ⅳ,AST)是中药黄芪的主要活性成分之一,但由于AST的疏水性特征限制了其生物利用度。在本实验中,我们开发了一种血小板膜修饰的poly (d, L-lactic-Co-Glycolic Acid)-block (PLGA-b)-poly (Ethylene Glycol)(PEG)-Triphenylphosphonium(TPP)(PLGA-b-PEG-TPP)聚合物纳米胶束用于包裹AST,从“器官-细胞器”层面实现“心脏-线粒体”的双重靶向功效。我们首先通过透射电镜、动态光散射、药物释放、稳定性考察等方法对载药纳米胶束进行了表征;采用活体成像法证实了载药纳米胶束的心脏靶向功效;运用小动物心脏超声、组织学、血清酶学考察了载药纳米胶束对缺血再灌注(Ischaemia/Reperfusion,I/R)后心脏功能和心肌损伤的影响;通过考察线粒体形态、膜电位、活性氧(Reactive Oxygen Species,ROS)以及血清和心脏中炎症因子水平,评价了载药纳米胶束对心脏线粒体功能和炎症的影响,实验结果显示,相较于游离的黄芪甲苷,载药纳米胶束显著改善了I/R后心脏功能、心肌损伤、线粒体损伤以及心脏炎症,提示载药纳米胶束显著改善了AST的生物利用度和心脏保护活性。本实验的开展为疏水性中药活性单体的递送提供了一种全新策略。

Acute myocardial infarction(AMI) is a serious threat to human health due to its high morbidity and mortality. Persistent myocardial injury remains after AMI, although the mortality of AMI has been greatly reduced by drugs, interventional therapy and surgery. Astragaloside Ⅳ(AST) is one of the main active components of Astragali Radix. However, the hydrophobicity of AST limits its bioavailability. In this experiment,we developed a platelet membrane-modified poly(d, L-lactic-Co-Glycolic Acid)-block(PLGA-b)-poly(Ethylene Glycol)(PEG)-Triphenylphosphonium(TPP)(PLGA-b-PEG-TPP) polymer nanomicelles for encapsulating AST to achieve the dual targeting effect of ’ heart-mitochondria ’ from the ’ organ-organelle ’ level. In this study, the drugloaded nanomicelles were characterized by transmission electron microscope, dynamic light scattering, drug release and stability investigation. The cardiac targeting effect of drug loaded nanomicelles was confirmed by in vivo imaging. The effects of drug-loaded nanomicelles on cardiac function and myocardial injury after I/R were investigated by echocardiography, histology and serum enzymology. The effects of drug-loaded nanomicelles on cardiac mitochondrial function and inflammation were evaluated by examining mitochondrial morphology,membrane potential, reactive oxygen species(ROS)and levels of inflammatory factors in serum and heart.Compared with the free AST, the results showed that drug-loaded nanomicelles significantly improved cardiac function, myocardial injury, mitochondrial damage and cardiac inflammation after I/R. It was suggested that the drug loaded nanomicelles significantly improved the bioavailability and cardioprotective activity of AST. This experiment provides a new strategy for the delivery of hydrophobic active monomer of traditional Chinese medicine.