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

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.

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。

活性氧（ROS）过量生成与诸多炎性疾病的发生发展息息相关，研究ROS响应性载体材料对于氧化应激损伤相关疾病的靶向诊疗具有重要意义。为解决现有材料的不足，本项目设计并合成了一系列基于β-环糊精（β-CD）的ROS响应性材料（OxbCDs），其中响应性基团为苯硼酸频哪醇酯（PBAP），通过PBAP结构和合成过程可以方便地调控最终材料的ROS敏感性和水解周期。以OxbCDs制备了纳米粒，初步阐明了材料结构与其体内外响应性水解和释药特性间的相关性；系统地评价了不同ROS响应性纳米粒的体内外安全性，揭示了材料分子结构对其影响。基于此，以动脉粥样硬化（AS）为疾病模型，选择载脂蛋白E基因敲除小鼠建立了AS模型，以雷帕霉素（RAP）为模型药物，研究了ROS响应纳米粒对AS斑块的靶向性和ROS响应性RAP纳米药物防治AS的有效性；结果证明了ROS响应性RAP纳米药物比非响应性纳米药物具有更显著的疗效，能有效减小AS斑块面积，并稳定AS斑块。同时，研究了ROS响应性RAP纳米药物防治腹主动脉瘤（AAA）的效果；在证明响应性纳米药物靶向治疗AAA效果的基础上，通过引入靶向肽cRGDfK、同时引入cRGDfK和巨噬细胞膜的逐级靶向化策略进一步增加了ROS响应性纳米粒对AAA病灶的靶向性，进而有效提高了对应纳米药物靶向防治AAA的疗效。此外，以除核酵母微囊结合自组装RAP纳米药物构建了具有口服AS靶向特性的递药系统，阐明了其对远端炎性病灶的靶向机制，明确了其口服靶向治疗AS的有效性。另一方面，体内外实验证实了以OxbCD制备的纳米粒可以通过清除过氧化氢实现抗氧化应激和抗炎的效果，而通过OxbCD纳米粒和抗炎药物的协同作用能够实现更加理想的抗炎作用。基于此，通过将PBAP和Tempol同时引入β-CD得到了具有广谱ROS清除性能的新材料，证明了其纳米粒具有更加优异的抗炎活性。通过鲁米诺键合材料构建了髓过氧化物酶响应性自发光纳米探针，可用于中性粒细胞相关急性炎症性疾病的实时动态成像。上述成果为构建ROS响应性释药系统提供了优异的载体材料，为设计性能更加优良的ROS响应性材料提供了实验基础，同时已构建的炎症微环境响应性靶向释药系统有望用于防治AS及其他炎性血管疾病。