Nerve Growth Factor Nanoparticles to Cross the Blood-Brain Barrier

神经生长因子纳米粒子跨越血脑屏障

• 批准号: 8679894
• 负责人: Xiaowei Dong
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679894
• 关键词: Address; Animal Model; Biological; Biological Testing; Blood - brain barrier anatomy; Brain; Capillary Endothelial Cell; Cells; Central Nervous System Agents; Central Nervous System Diseases; Chemistry; Cholesterol Esters; Clinical; Clinical Research; Complex; Development; Diffusion; Drug Formulations; Engineering; Environment; Feasibility Studies; Goals; Health; Health Sciences; High Density Lipoproteins; In Vitro; Ions; Lipids; Maintenance; Mediating; Modeling; Nanotechnology; Nerve Growth Factors; Neuraxis; Neurons; Neuropharmacology; Neurosciences; Operative Surgical Procedures; Penetration; Peptides; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Polyethylene Glycols; Protamines; Research Project Grants; SR-BI receptor; Science; Source; Statistical Methods; Surface; System; Technology; Testing; Texas; Therapeutic; Tocopherols; Toxic effect; Universities; Vitamin E; Water; Yang; alpha-tocopheryl polyethylene glycol succinate; apical membrane; base; cholinergic neuron; design; drug development; innovation; lipophilicity; nanoparticle; new technology; novel; prevent; receptor; research study; transcytosis; uptake; vitamin E succinate

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.

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400 Da的亲脂性分子才能穿过BBB。缺乏有效的递送技术阻碍了超过95%的分子用于CNS药物开发。受体介导的转运系统用于递送药物穿过BBB。I型B类清道夫受体（SR-BI）在脑毛细血管内皮细胞的顶膜处高度表达，并通过受体介导的转胞吞作用促进高密度脂蛋白（HDL）相关胆固醇酯和α-生育酚的选择性摄取。我们先前开发了基于脂质的纳米颗粒，其在纳米颗粒表面上含有d-α-生育酚聚乙二醇1000琥珀酸酯（维生素E TPGS），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具有巨大的治疗潜力。我们现在建议修饰纳米颗粒并制备HDL模拟α-生育酚包覆的NGF纳米颗粒以靶向大脑。这种新型的纳米颗粒将使用天然HDL的组分制备，并用维生素E TPGS包覆。将通过离子对策略将NGF掺入纳米颗粒中。将评价最佳的NGF纳米颗粒的生物活性和通过SR-BI介导的转胞吞作用穿过BBB的能力。