Cardiac-targeted and ROS-responsive liposomes containing puerarin for attenuating myocardial ischemia-reperfusion injury

<b>Aim:</b> This study aimed to construct an ischemic cardiomyocyte-targeted and ROS-responsive drug release system to reduce myocardial ischemia-reperfusion injury (MI/RI). <b>Methods:</b> We constructed thioketal (TK) and cardiac homing peptide (CHP) dual-modified liposomes loaded with puerarin (PUE@TK/CHP-L), which were expected to deliver drugs precisely into ischemic cardiomyocytes and release drugs in response to the presence of high intracellular ROS levels. The advantages of PUE@TK/CHP-L were assessed by cellular pharmacodynamics, <i>in vivo</i> fluorescence imaging and animal pharmacodynamics. <b>Results:</b> PUE@TK/CHP-L significantly inhibited apoptosis and ferroptosis in H/R-injured cardiomyocytes and also actively targeted ischemic myocardium. Based on these advantages, PUE@TK/CHP-L could significantly enhance the drug's ability to attenuate MI/RI. <b>Conclusion:</b> PUE@TK/CHP-L had potential clinical value in the precise treatment of MI/RI. Myocardial ischemia-reperfusion injury (MI/RI) is a series of pathological changes caused by revascularisation after myocardial infarction, for which there is no effective treatment. Excessive production of reactive oxygen species (ROS) is an important predisposing factor for MI/RI. Apoptosis and ferroptosis of cardiomyocytes are important pathological mechanisms of myocardial ischemia-reperfusion injury and both are closely related to excessive intracellular ROS. We have successfully synthesized ROS-responsive and cardiac-targeted liposomes loaded with puerarin (PUE@TK/CHP-L). It was found that PUE@TK/CHP-L could target ischemic myocardium. <i>In vivo</i> and <i>ex vivo</i> results showed that PUE@TK/CHP-L can effectively reduce the level of myocardial oxidative stress and decrease cardiomyocyte apoptosis and ferroptosis. These results suggested that PUE@TK/CHP-L could hopefully be a promising drug carrier for mitigating MI/RI.

**研究目的**：本研究旨在构建一种靶向缺血心肌细胞且响应活性氧簇(Reactive Oxygen Species, ROS)的药物递送系统，以减轻心肌缺血再灌注损伤(MI/RI)。
**研究方法**：我们构建了负载葛根素的硫缩酮(thioketal, TK)与心脏归巢肽(cardiac homing peptide, CHP)双修饰脂质体（PUE@TK/CHP-L），该制剂可精准递送药物至缺血心肌细胞，并在细胞内高活性氧簇水平下触发药物释放。本研究通过细胞药效学、体内(in vivo)荧光成像及动物药效学实验，对PUE@TK/CHP-L的优势进行了评价。
**研究结果**：PUE@TK/CHP-L可显著抑制缺氧/复氧(Hypoxia/Reoxygenation, H/R)损伤心肌细胞的凋亡与铁死亡，同时可主动靶向缺血心肌组织。基于上述优势，PUE@TK/CHP-L能够显著提升药物减轻MI/RI的效果。
**研究结论**：PUE@TK/CHP-L在MI/RI的精准治疗中具有潜在临床应用价值。

心肌缺血再灌注损伤(MI/RI)是心肌梗死后血管重建引发的一系列病理变化，目前尚无有效治疗手段。活性氧簇过量生成是MI/RI的重要易感因素。心肌细胞凋亡与铁死亡是MI/RI的关键病理机制，且二者均与细胞内过量活性氧簇密切相关。本研究成功合成了负载葛根素的ROS响应型心肌靶向脂质体PUE@TK/CHP-L。研究发现，PUE@TK/CHP-L可靶向缺血心肌组织。体内(in vivo)及离体(ex vivo)实验结果表明，PUE@TK/CHP-L可有效降低心肌氧化应激水平，减少心肌细胞凋亡与铁死亡。上述结果提示，PUE@TK/CHP-L有望成为减轻MI/RI的理想药物递送载体。