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-?-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), a water-soluble source of ?- 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 ?-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.

Public Health Relevance

The blood-brain barrier is a diffusion barrier essential for the normal function of the central nervous system, which impedes most compounds entering the brain and obstructs the drug development for central nervous system disorders. Therefore, we will develop novel nanoparticles to facilitate the delivery of nerve growth factor to cross the blood-brain barrier via a receptor-mediated transport system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
1R03NS087322-01
Application #
8679894
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Bosetti, Francesca
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$73,000
Indirect Cost
$23,000
Name
University of North Texas
Department
None
Type
Schools of Pharmacy
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107