活性氧响应性材料的设计与合成及其释药系统在动脉粥样硬化治疗中的应用研究

项目名称： 活性氧响应性材料的设计与合成及其释药系统在动脉粥样硬化治疗中的应用研究

项目编号： No.81471774

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张建祥

作者单位： 中国人民解放军第三军医大学

项目金额： 75万元

中文摘要： 设计开发生物化学信号响应性材料和释药系统是药物载体研究的重要领域。机体产生的过量活性氧（ROS）与心血管疾病等重大疾病息息相关，故ROS响应性释药系统对防治此类疾病意义重大。缺乏具有优异ROS响应性和良好体内相容性的材料是该领域面临的主要瓶颈问题。本项目拟在已有研究基础上，设计并合成一系列ROS响应性环糊精材料；通过响应性单元苯硼酸酯的结构设计和合成控制调节最终材料的ROS敏感性；以合成的材料制备纳米粒，研究材料分子结构与其ROS响应性间的相关性；深入评价其体内外生物相容性，阐明材料结构对其体内安全性的影响。基于此，以与ROS损伤密切相关的动脉粥样硬化（AS）为代表性疾病，建立小鼠AS模型，研究不同ROS响应性的普罗布考抗氧化纳米药物的被动靶向效应及其治疗AS的有效性；结合细胞水平生物学评价，揭示材料结构性能与其释药系统疗效间的关系。为设计性能更加优异的ROS响应性材料提供指导和依据。

中文关键词： 药物载体；纳米载体；药物控释；靶向治疗；动脉粥样硬化

英文摘要： Design and development of chemically/biologically responsive materials and delivery systems are important areas in the field of pharmaceutical materials. Overproduced reactive oxygen species (ROS) in the organism are intimately correlated with many important diseases like cardiovascular disease, and therefore ROS-responsive drug delivery systems are particularly intriguing for the treatment of these ROS-related diseases. However, the absence of materials with elegant ROS-sensitivity and excellent in vivo biocompatibility is the key issue limiting the progress in this field. Based on our previous studies, this proposal aimed to design and synthesize a series of ROS-responsive cyclodextrin materials. The ROS-sensitivity of resulting materials may be tailored by the chemical structure of responsive phenylboronic acid esters and synthesis controlling. The newly prepared materials will be employed to fabricate nanoparticles, to elucidate the correlation between the molecular structure of obtained materials and their ROS sensitivity. Furthermore, intensive studies will be carried out to evaluate in vitro and in vivo biocompatibility of ROS-sensitive nanoparticles, and illuminate the influence of materials structure on their in vivo safety. On the basis of these studies, atherosclerosis (AS) will be used as a representative disease model. By establishing an AS model in mice, we may examine passive targeting effect and therapeutic activity of probucol-containing antioxidative nanomedicines with various ROS-sensitivities. Combined with cellular experiments, these studies may address the relationship between the structure/properties of ROS-sensitive materials and the efficacy of their delivery systems. Overall, this research may provide valuable insight and guidance for designing ROS-responsive materials with more excellent characteristics.

英文关键词： Drug carrier;Nanovehicle;Controlled drug delivery;Targeted therapy;Atherosclerosis