新型纳米粒-微泡复合体靶向介导MaFGF治疗心力衰竭的实验研究

Heart failure (HF) has become an important public health problem seriously threating human life and health. Myocardial apoptosis and oxidative stress play an important roles in the myocardial remodeling and the occurrence and development of HF. Previous studies had confirmed that acidic fibroblast growth factor (aFGF) can reduce the apoptosis of myocardial cell and improve the myocardial antioxidant capacity, and modified acidic fibroblast growth factor (MaFGF) is equivalent to aFGF’s myocardial protection effect while eliminates its possibility of cancer. So the application of MaFGF in treatment of HF has a very huge potential,but due to the lack of efficient, safe, controllable myocardial targeted delivery carrier limits the application of MaFGF. This project, based on the previous studies,intends to combine with the advantages of both nanoparticles and microbubbles, sought to construct a complex of MaFGF-loaded nanoparticles and phospholipid-based microbubbles , which will be used as targeted carriers to deliver MaFGF to rats with heart failure combining with ultrasound targeted microbubble destruction(UTMD), and the treatment effects will be evaluated with conventional echocardiography, speckle tracking imaging and cardiac catheterization, also explore the possible cellular and molecular mechanism, to provide new ideas and scientific evidences for the clinic treatment of heart failure in future.

心力衰竭（HF）已经成为严重威胁人类生命健康的重要公共卫生问题。心肌细胞凋亡、氧化应激等在心肌重构及HF的发生及进展中起着重要的作用。前期研究证实，酸性成纤维细胞生长因子（aFGF）可以减少心肌细胞凋亡，提高心肌抗氧化能力，改构型酸性成纤维细胞生长因子（MaFGF）具有与aFGF同等的心肌保护效应，且可避免野生型aFGF可能产生的致癌等毒副作用，因此MaFGF用于治疗HF有巨大的潜力，然而由于缺乏高效、安全、可控的心肌靶向递送载体限制了其应用。本项目在前期研究基础上, 拟构建一种新型携载MaFGF的纳米粒-微泡复合体，经外周静脉注射入心衰大鼠体内并结合超声微泡靶向破裂技术，将 MaFGF 靶向递送至心肌组织而发挥作用；用常规超声心动图、斑点追踪成像及心导管等技术评该方法对HF的治疗效果，并采用免疫组化、细胞与分子病理学等方法探讨其可能机制。为今后心衰的治疗研究提供新的思路和依据。

心力衰竭（HF）是各种病因所致心脏疾病的终末阶段，严重威胁人类生命健康。然而，目前临床上HF的治疗仍存在诸多问题和挑战。本项目在前期研究基础上, 成功制备了新型携载FGF（包括MaFGF和aFGF）的纳米粒、阳离子脂质微泡（CPMBs）及新型纳米粒-阳离子脂质微泡复合体；分别应用不同形式的MaFGF 和aFGF对阿霉素心肌损伤大鼠及DM大鼠进行干预，观察新型携载FGF（MaFGF和aFGF）纳米粒结合超声靶向微泡破裂技术(UTMD)对阿霉素HF及糖尿病心肌病（DCM）的防治效果，并探讨相关作用机制。研究结果证实：应用新型纳米粒结合微泡空化靶向介导MaFGF和aFGF能够有效防治阿霉素诱导的心肌损伤及糖尿病心肌病，保护左心室收缩功能；与其他形式FGF干预组相比，新型携载FGF（包括MaFGF和aFGF）纳米粒结合UTMD组对心肌损伤的防治效果最明显。相关作用机制可能是：新型携载FGF纳米粒结合UTMD可将FGF靶向高效递送至病变心肌而发挥作用，MaFGF和aFGF可减轻ROS对心肌线粒体膜损伤，提高心肌抗氧化能力，抑制氧化应激反应并减缓心肌纤维化的形成，还可通过激活PI3K/Akt信号通路减少心肌细胞凋亡；另外，aFGF可通过促进心肌微血管新生、改善心肌微循环而保护心肌功能。该技术方法有望成为临床防治HF的新策略，具有重要的科学意义和良好应用前景。