以提高纳米载体跨血脑屏障转运为基础的阿尔茨海默症靶向递药系统构建和评价

A key issue in brain targeting drug delivery is the poor efficiency in transportation through blood brain barrier (BBB). In this project, a kind of novel Alzheimer’s disease (AD) targeted drug delivery system, BACE1-D-p@DGL-MAN-H6, is designed with actively BBB targeting capacity, highly intracellular transportation and brain side exocytosis ability. The system could actively target transferrin receptor on BBB by H6 peptide and then mediate endocytosis. In the acidic lysosomes, the system will quickly disassociate from the H6-transferrin receptor complex due to the sensitive bond between H6 peptide and the system. Then the system will escape from endosomes and be excytosed to brain mediated by the MAN on the system because of its high binding affinity with glucose transporter on the internal side of cell membrane. Furthermore, the MAN could actively target neuro glial cells due to highly expressed glucose transporter. After internalization, the BACE1 siRNA and tau-binding D-p peptide would be released to overcome the two major symptoms of AD, resulting in good treatment outcome.

本项目针对跨血脑屏障药物递送面临的跨膜转运效率差的关键科学问题，设计了具有血脑屏障主动靶向能力、良好细胞内转运和向脑侧外排能力的递药系统BACE1-D-p@DGL-MAN-H6，用于阿尔茨海默症的靶向药物递送和治疗。该系统在H6多肽的介导下，主动靶向血脑屏障上高表达的转铁蛋白受体并与之结合后介导入胞，进而在溶酶体微酸环境中递药系统与H6多肽-转铁蛋白受体复合物脱离，从而快速逃离溶酶体，并通过MAN与细胞膜内侧的葡萄糖转运体结合，促进其向脑侧转运。入脑后，进一步通过神经胶质细胞高表达的葡萄糖转运体进入神经胶质细胞，释放针对Aβ的BACE1 siRNA和抑制tau蛋白过度磷酸化的D-p多肽，协同发挥阿尔茨海默症治疗效果。该设计依据跨血脑屏障递药系统转运存在的关键问题，有效提高递药系统在跨膜转运各步骤的效率，从而显著提高其脑部疾病的靶向递送效果，相关思路未见报道，具有较高的研究价值和应用意义。