重组高密度脂蛋白载药系统的构建及其变构动力学和多效应归一化量效关系的研究

The present work will concern the development of reconstituted high density lipoprotein (rHDL) to serve as a novel delivery vehicle for cardiovascular drug due to the attractive attributes of HDL including unique circulating route and metabolic pathway, the function in reverse cholesterol transport, the prevention or reversal of atherosclerosis and vascular protective action. This optimized rHDL are expected to exert a better effect on drug delivery to atherosclerotic lesions on vascular wall as well as therapeutic effect of carrier..Based on our formal achievement in "SGER", we will further investigate the influence of biological excipients such as lipid materials and apolipoproteins on the structure, stability and mimetic properties of drug carrier. And the allosteric dynamics of reconstituted HDL vehicle and its effect on the targeting delivery as well as synergy efficacy will also be studied. Given the progression and medication of atherosclerosis disease, the method to evaluate the synergy efficacy of carrier and drug, and the dose-effect relationship between them will be established. It will provide a way of thinking and method for the design and improvement of the drug delivery system, and solve the key basic issues during its constitution. The outcome of this research will supply a full and accurate evidence for further understanding the value of rHDL as a novel drug delivery system, and for extending its applications as well.

根据高密度脂蛋白（HDL）体内独特的巡行与代谢路线、逆向转运胆固醇作用以及抗动脉粥样硬化和血管保护功能等生物学特性，将HDL的组成成份进行重组和优化，作为一种新型的载药系统，用来包载治疗心血管疾病的药物，期待在体内具有更好的向血管壁粥样硬化病灶区域传输的特性及治疗作用。. 在前期"探索性项目"研究成果的基础上，进一步探讨脂质材料和载脂蛋白等生物功能辅料对载药系统的构造、稳定性以及仿生功能的影响，研究重组HDL载药系统的变构动力学及其与靶向递药和协同增效的相关性。根据动脉粥样硬化的发病进程和用药特点，建立反映载体和药物协同作用的评价方法、载体和药物与药效之间的量效关系，为药物载体的设计和完善提供思路和方法。.本项目的研究成果将为解决重组HDL载药系统构建中的关键基础问题，进一步了解重组高密度脂蛋白作为新型药物载体的运作价值以及拓展其应用范围提供翔实有力的科学依据。

本项目在前期“探索性项目”研究成果的基础上，以心血管药物为模型药物，进一步探讨脂质材料和载脂蛋白等生物功能辅料对载药系统的构造、稳定性以及仿生功能的影响，研究重组HDL载药系统的变构动力学及其对靶向递药和协同增效的作用。根据动脉粥样硬化的发病进程和用药特点，建立反映载体和药物协同作用的评价方法、载体和药物与药效之间的量效关系。对重组HDL进行配体修饰和结构改造，在改善其生理功能的同时，提高斑块靶向效率。. 研究结果表明，脂肪酸的修饰可降低盘状重组HDL与卵磷脂胆固醇酰基转移酶的反应活性，减少药物泄漏，提高疗效；透明质酸、硫酸葡聚糖的修饰进一步提高了药物在斑块的蓄积量，采用壳核结构增强了载体介导胆固醇外流的生理功能；运用中效原理证明重组HDL与包载的药物具有显著的协同治疗作用。. 项目研究成果如下：.1、撰写SCI论文并投稿10篇，其中发表7篇，接收1篇；.2、申请发明专利2项，其中授权1项，公开1项；.3、主办或参与国际学术交流4次、国内学术交流4次，发表会议论文6篇。. （详见附件）