靶向、多功能纳米胶束-QC抑制剂的制备及协同抗阿尔兹海默症作用研究

阿尔兹海默症（AD）特效治疗药物研发迫在眉睫，血脑屏障（BBB）是阻碍药物进入脑部的主要原因。新型药物载体，特别是靶向传递分子、兼具抗AD活性的纳米载体，可高效透过BBB将药物跨膜转运至脑部，实现精准给药，同时提升疗效。而葡萄糖基化修饰能使纳米载体靶向识别AD患者脑部血管内皮细胞葡萄糖转运受体-1（GluT-1），引入硒则可赋予载体抗AD作用等。为此，本项目拟设计、合成糖基化多聚硒代氨基酸纳米胶束，明确其构效关系；并以此靶向、多功能纳米载体包裹前期工作中发现的谷氨酰胺酰基环化酶（QC）抑制剂，阐明纳米胶束-抗AD活性分子的稳定性、生物学功能和靶向跨膜转运、控释动力学行为等；在此基础上，系统研究该先导药物在模型小鼠体内的靶向性能、抗AD作用及机理等，揭示纳米胶束和QC抑制剂抗AD功能的协同增强机制。本项目将为新型纳米药物载体研究奠定重要基础，对创新抗AD药物开发具有重大理论意义和应用价值。

Alzheimer's disease (AD) is an irreversible, complex and progressive neurodegenerative disorder. Blood-brain barrier (BBB), a complex tight endothelial vascular lining, is the great challenge for the development of anti-AD agents. Novel delivery systems such as nanoparticles and micelles are applied to overcome the limitations. But few nanocarriers can enter the brain via a systemic route through the BBB to efficiently reach neurons. In the current study, a self-assembled micelle with a surface featuring properly configured glucose will be prepared based on the synthesis of a series of copolymers containing poly(amino acid)s and poly(Selenium-containing amino acid)s. The BBB crossing of this nanocarrier will be boosted by the up-regulated glucose transporter-1 (GluT-1) in AD brain capillary endothelial cells. Meanwhile, this multi-functional nanocarrier will exhibit notable anti-AD effects because of the antioxidant and free radical scavenging abilities of Se. To explore the application of this nanocarrier in the development of anti-AD agents, glutaminyl cyclase inhibitor will be loaded on the glucosylated poly(Selenium-containing amino acid)s micelle, and structure, property and function of this novel agents will be assessed. Furthermore, we will explore the anti-AD effects of glucosylated poly(Selenium-containing amino acid)s micelle loaded with glutaminyl cyclase inhibitor in AD model mice deeply. Synergetic effects in vitro and in vivo of glucosylated poly(Selenium-containing amino acid)s micelle and glutaminyl cyclase inhibitor in bioactive substances delivery across BBB and anti-AD potency will be discussed here.