Drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Opiate and HIV target areas in brain such as basal ganglia and cortex that are enriched in 5 opioid receptors. Previous studies have shown that opiates act synergistically with HIV proteins (Tat and gp120) to potentiate HIV- related neurotoxicity, which ultimately leads to progression of NeuroAIDS. Currently, there is no treatment available to alleviate the synergistic effects of opiates and HIV, especially due to impenetrability of therapeutic molecules across the blood brain barrier (BBB). Therefore development of a drug delivery system containing an 5 opioid antagonist, a neuroprotective agent and ART that can cross BBB may have significant therapeutic advantage for treatment of opiate addiction and NeuroAIDS. In recent years, nanoparticle based delivery systems have shown promising approach for drug targeting to the brain. In the present proposal, we will develop a unique magnetically guided nanocarrier bound to CTOP (BBB impenetrable In Specific Aim 1 (b) the developed formulation will be tested in vitro for its ability to transmigrate across BBB. Finally, in Specific Aim 2 we will evaluate the in vivo efficacy of the developed nanocarrier in an HIVE SCID morphine mouse model. The efficacy parameters will be antiretroviral efficacy, neuropathology, neuroprotection and morphine related behaviors in mouse. Based on our preliminary study which shows that AZTTP binds significantly to nanoparticles and it inhibits viral replication in PBMCs, we propose that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction and NeuroAIDS.

Public Health Relevance

This application has significant relevance to the purpose of the PAS-08-186, drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Currently, there is no treatment available to alleviate the synergistic neurotoxicity of opiates and HIV, especially due to impenetrability of therapeutic molecules across the BBB. This project will evaluate a novel magnetically guided nanocarrier drug delivery system for simultaneous targeting of CTOP, BDNF and AZTTP across the BBB, thereby reduce opiate addiction and also NeuroAIDS in HIV infected subjects who are opiate users.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA027049-05
Application #
8468152
Study Section
Special Emphasis Panel (ZRG1-AARR-H (02))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$677,521
Indirect Cost
$168,315
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
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