Nerve Growth Factor Nanoparticles to Cross the Blood-Brain Barrier

描述(申请人提供)：血脑屏障(BBB)是治疗中枢神经系统(CNS)疾病药物开发的瓶颈。只有小于400Da的亲脂分子才能通过血脑屏障。缺乏有效的递送技术阻碍了超过95%的中枢神经系统药物开发的分子。受体介导的转运系统被用来通过血脑屏障输送药物。B型清道夫受体(SR-BI)高表达于脑毛细血管内皮细胞顶膜，通过受体介导的跨细胞作用促进高密度脂蛋白相关胆固醇酯和α-生育酚的选择性摄取。我们之前开发了基于脂质的纳米颗粒，在纳米颗粒的表面含有d-α-生育酚聚乙二醇1000琥珀酸酯(维生素ETPGS)，它是α-生育酚的一种水溶性来源。神经生长因子(NGF)对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是必不可少的。NGF对多种中枢神经系统疾病具有巨大的治疗潜力。我们现在建议对纳米颗粒进行修饰，并制备高密度脂蛋白模拟α-生育酚包裹的神经生长因子纳米颗粒来靶向大脑。这种新型纳米粒子将使用天然高密度脂蛋白的成分制备，并包裹有维生素E和三磷酸甘油。NGF将通过离子对策略被整合到纳米颗粒中。最优的NGF纳米颗粒的生物学活性和通过SR-BI介导的细胞转运穿越血脑屏障的能力将被评估。

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.