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

基本信息

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
项目类别：
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

项目摘要

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（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。技术阻止了超过 95% 的中枢神经系统药物开发分子被用于跨 BBB 传递药物。脑毛细血管内皮细胞的顶膜，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。乙二醇 1000 琥珀酸酯（维生素 E TPGS），一种水溶性 α-生育酚来源，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，现在我们对各种中枢神经系统疾病具有巨大的治疗潜力。建议对纳米颗粒进行修饰并制备模拟 HDL 的 α-生育酚涂层 NGF 纳米颗粒，以靶向大脑。这种新型纳米颗粒将使用天然 HDL 和涂层的成分来制备。将通过离子对策略将 NGF 掺入纳米颗粒中，并通过 SR-BI 介导的转胞吞作用评估最佳 NGF 纳米颗粒的生物活性和穿过 BBB 的能力。