The major limitation of the currently used anti-HIV drugs such as protease inhibitors is their poor passage through the blood-brain barrier to the center nervous system, which acts as a hidden cellular reservoir for HIV-I. The poor permeability of these agents is considered to be due to the efflux action of the membrane associated MDR1 multidrug transporter, p-glycoprotein (P-gp). Furthermore, the high drug protein binding of protease inhibitors limits the free drug available in the serum for uptake by the brain. In this study, we propose to investigate TAT-peptide conjugated nanoparticles as a delivery mechanism to enhance the CNS delivery of anti-HIV drugs. Nanoparticles in our study are extremely small biodegradable colloidal particles (20 to 40 nm in diameter) with a therapeutic agent encapsulated (entrapped) in the polymer matrix. The hypothesis of the proposed research is that a TAT-peptide conjugated to nanoparticles would increase their permeability across the BBB and hence the transport of the encapsulated drug to the CNS. Nanoparticles once localized in the CNS would release the encapsulated therapeutic agent slowly due to their biodegradation. Thus, it is anticipated that the nanoparticle-mediated drug delivery would enhance the CNS bioavailability of the drug as well as its retention, which would enhance the therapeutic efficacy of the drug.
The specific aims are to test the hypotheses that the -i) TATconjugated nanoparticles bypass the efflux action of the membrane bound P-gp and ii) TATconjugated nanoparticles result in greater CNS delivery and sustained drug retention than that with drug in solution. The successful outcome of the proposed approach could provide a novel modality to deliver several classes of therapeutic agents including anticancer agents, proteins, peptides, and genes to the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH067525-01A2
Application #
6746473
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2003-12-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$220,500
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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