Nerve Growth Factor Nanoparticles to Cross the Blood-Brain Barrier

描述（由申请人提供）：血脑屏障（BBB）是中枢神经系统（CNS）疾病药物开发的瓶颈。只有小于400da的亲脂分子才能穿过血脑屏障。缺乏有效的递送技术阻碍了95%以上用于中枢神经系统药物开发的分子。受体介导的转运系统被用于通过血脑屏障输送药物。清道夫受体B类I型（SR- BI）高表达于脑毛细血管内皮细胞顶膜，并通过受体介导的胞饮作用促进高密度脂蛋白（HDL）相关胆固醇酯和a-生育酚的选择性摄取。我们之前在NPs表面开发了含有d-α-生育酚聚乙二醇1000琥珀酸酯（维生素E TPGS）的脂质纳米颗粒，这是α-生育酚的水溶性来源。神经生长因子（NGF）对于周围神经系统神经元的发育和表型维持以及中枢神经系统胆碱能神经元的功能完整性至关重要。神经生长因子对各种中枢神经系统疾病有很大的治疗潜力。我们现在提议修改纳米颗粒，并制备模拟高密度脂蛋白α-生育酚包被的NGF纳米颗粒来靶向大脑。这种新型纳米颗粒将使用天然高密度脂蛋白的成分制备，并涂覆维生素E TPGS。NGF将通过离子对策略被纳入纳米颗粒中。最佳的NGF纳米颗粒将通过sr - bi介导的胞吞作用来评估其生物活性和穿越血脑屏障的能力。

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is the bottleneck in drug development for central nervous system (CNS) disorders. Only lipophilic molecules of less than 400 Da can cross the BBB. The lack of efficient delivery technologies prevents over 95% of molecules for CNS drug development. Receptor-mediated transport systems were used to deliver drugs across the BBB. Scavenger receptor class B type I (SR- BI) is highly expressed at the apical membrane of brain capillary endothelial cells, and facilitates selective uptake of high-density lipoprotein (HDL)-associated cholesteryl ester and a-tocopherol by receptor-mediated transcytosis. We previously developed the lipid-based nanoparticles that contain d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), a water-soluble source of α- tocopherol, on the surface of the NPs. Nerve growth factor (NGF) is essential for the development and phenotype maintenance of neurons in the peripheral nervous system and for the functional integrity of cholinergic neurons in the CNS. NGF has great therapeutic potentials for various CNS disorders. We now propose to modify the nanoparticles and prepare HDL-mimicking α-tocopherol-coated NGF nanoparticles to target the brain. The novel nanoparticles will be prepared using the components of natural HDL and coated with vitamin E TPGS. NGF will be incorporated into the nanoparticles by an ion-pair strategy. The optimal NGF nanoparticles will be evaluated for the biological activity and the ability to cross the BBB by SR-BI-mediated transcytosis.