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, and limitations in biodistribution and pharmacokinetic drug patterns. Despite advances in ART and its abilities to cause significant reductions in cerebrospinal fluid viral loads;NeuroAIDS morbidities continue on the rise. A principal issue obstacle in achieving maximal clinical responses is in maintaining high ART drug levels in disease affected brain subregions. To address this issue, we will develop nanformulations of commonly used anti-retroviral drugs (lopinavir, ritonavir, and efavirenz) and deliver the drugs inside circulating blood-borne monocyte-macrophages. The means to improve distribution of ART across the BBB will require a three-step approach. 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 nonnucleoside 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 will be designed to specifically target macrophages. 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. In this way, the abilities of drug to bypass the reticuloendothelial system and cross the BBB will be determined. High performance liquid chromatography analyses will be used to measure drug levels in spleen, lymph nodes, liver and brain in NP-treated mice and will provide confirmation of drug tissue penetrance. These tests will 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 human HIV-1 CNS disease. 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.

Public Health Relevance

The elimination of the human immunodeficiency virus inside its central nervous system sanctuary has not been achieved and HIV-1 dementia remains a public health problem. The reasons revolve around variable antiretroviral therapy (ART) penetrance across the blood-brain barrier as well as complex dosing regimens, costs, and drug toxicities. To address this issue, we plan to develop nanoformulations of commonly used ART with variable brain entry profiles and deliver them directly to diseased brain tissue inside blood-borne macrophages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036126-16
Application #
8242026
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1996-12-01
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
16
Fiscal Year
2012
Total Cost
$457,076
Indirect Cost
$146,140
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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