The elimination of the human immunodeficiency virus inside its central nervous system (CNS) sanctuary is affected by variable antiretroviral therapy (ART) penetrance across the blood-brain barrier (BBB), complex dosing regimens, costs, toxicities, biodistribution, and pharmacokinetic patterns of drug regimens. Despite advances in ART resulting in reductions in cerebrospinal fluid viral loads, neuroAIDS morbidities continue on the rise. One principal issue is achieving robust ART drug levels in affected brain subregions and maintaining the levels. To address this issue, we will develop nanoformulations of commonly used anti-retroviral and adjunctive drugs (for example, Celecoxib) with variable CNS entry profiles and use established or more """"""""novel"""""""" means to deliver the drugs directly to diseased brain tissue captured inside blood-borne monocytes or macrophages. To this end, we will determine the means to maximize both the delivery and distribution of ART across the BBB. A three-step approach will be sought. First, comparative measures of nanoparticle (NP) drug formulations will be tested for entry and secretion into and from bone marrow-derived macrophages (BMM) and monocyte-derived macrophages (MDM). Here, viral protease and non-nucleoside reverse transcriptase inhibitor(s) will be packaged into phospholipids-coated NP. Cytotoxicity, anti-retroviral efficacy, mobility, and the functional consequences of macrophage carriage of the drug-laden particles will be measured. Second, pharmacokinetics (uptake, release, plasma, and tissue distribution) of the formulations will be investigated using BMM as a drug delivery system in mice. Third, ligand-formulated NP will be developed and tested in vitro then used to test direct intravenous administration in mice. Alternatively and to enhance NP entry into macrophages, formulations will be made with folate coatings and will be designed to specifically target macrophages, and as such, improve cell entry. Laboratory experiments reflecting immune activation of human monocytes and MDM will be developed to assess the optimal ways to enhance uptake of ligand-coated NP formulations. Thus, the abilities of drug to bypass the reticuloendothelial system and cross the BBB will be determined. High performance liquid chromatography analysis of spleen, lymph nodes, liver, and brain will provide confirmation of drug tissue penetrance and be used in tandem with histology and imaging assays. Lastly, the NP developed will be tested for anti-retroviral efficacy in affected brains of a primary and humanized mouse models of NeuroAIDS. All together, the goals are to enhance therapeutic efficacy and BBB migration of ART so that they can be translated for human use to improve disease outcomes in NeuroAIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS043985-09
Application #
8230866
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$216,598
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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