A Novel Method of Nanoparticle Delivery to Brain by Targeting Ec-gp96 ABSTRACT The blood brain barrier (BBB) is composed of brain microvascular endothelial cells connected each other with tight junction molecules thereby, making the barrier impermeable to toxins, bacteria, viruses, and other unwanted substance from blood. This specific characteristic feature of the BBB along with efflux pumps prevents the delivery of therapeutic compound to treat brain diseases. Although, several methods have been identified to target the central nervous system for drug delivery, non-specificity is a major problem with these strategies. One of the critical challenges in drug development is the delivery of drugs to the central nervous system (CNS) across the BBB. E. coli studies by Nemani group, performed using both an in vitro model of human brain microvascular endothelial cells and in newborn mice, have been used to identified a BBB specific receptor, Ec-gp96 to which E. coli K1, a meningitis causing bacterium binds and enters the brain. This interaction occurs between outer membrane protein A of E. coli and Ec-gp96 for binding to and entry of the BBB. The computer modeling studies of OmpA-Ec-gp96 interaction by Goddard group have predicted several compounds compatible with the binding to Ec-gp96. Of these several have been shown to be effective in preventing the binding of OmpA of E. coli with Ec-gp6 and thus inhibiting the invasion of the bacteria in HBMEC. This has identified for the first time small molecule ligands for Ec-gp96. Furthermore, Davis group has developed CDP nanoparticles to deliver drugs or other payloads to treat cancers and some of the methods are being tested in Phase I and Phase II clinical trials. These exciting experimental results set the stage for this proposal which will design Ec-gp96 targeting ligands and conjugate them to nanoparticles to develop a delivery system specifically targeting the blood-brain barrier.

Public Health Relevance

This proposal is aimed at designing ligands targeting a protein only found in the cells lining the blood-brain barrier, that will be used to make a drug-delivery system based on nanoparticles to specifically deliver drugs into the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071112-03
Application #
8246434
Study Section
Neurotechnology Study Section (NT)
Program Officer
Bosetti, Francesca
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$320,272
Indirect Cost
$77,171
Name
California Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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