This core will support pharmacokinetic (PK) studies for laboratory and animal nanoART investigations. In project 2, H. Gendelman mice will receive a single oral dose of individual nanoART drugs to characterize reference PK parameters. A starting single dose in mice will be scaled from the dose recommended in humans based on body-surface area (shape factor) normalization. PK, tissue distribution, blood brain barrier (BBB) penetration, and toxicity will be compared between the nanoART and free drug. Next, both nanoART and free ART will be administered to two models of infected mice as a part of a dose efficacy study. Plasma and target tissue concentrations will be determined. In project 3, multiple dose PK studies similar to that in mice will be performed in uninfected monkeys. A starting single dose in monkeys will be scaled from the dose recommended in humans based on body-surface area (shape factor) normalizations. PK parameters and linearities will be assessed by comparing PK results across dosing ranges. PK, tissue distribution, BBB penetration, and toxicity will be compared between the nanoART and free ART. Next, multiple dose efficacy studies will be performed in rhesus monkeys. The multiple dosing efficacy study will aim to achieve and maintain systemic exposure levels similar to that recommended in humans without exceeding the peak exposure levels reported in humans. The multiple dosing regimen will be designed from the single dose PK parameters. Hematology and chemistry panels will be monitored, and plasma drug concentrations measured for up to 14 weeks following multiple drug administration. Monkeys will be closely monitored for adverse events including blood pressure, pulse and cardiac rhythm, liver enzymes and renal function, and potential infusion reactions. In addition to close monitoring of safety parameters and PK analyses, the animals will undergo cerebrospinal fluid evaluations of HIV viral load and neuroinflammatory biomarkers at baseline and eight weeks on study (H. Fox, project 3). The long-term goal is to develop injectable nanoART for human use. If successful the work could lead to novel formulations that improve medication adherence, and thereby therapeutic outcomes, and novel treatment applications to include enhanced penetration into viral sanctuaries as the central nervous system. This core is already operative and has generated the preliminary data shown in project 2 (H. Gendelman) supporting the abilities to integrate each of the projects into one program.

Public Health Relevance

;The goal of attaining long acting antiretroviral therapies for HIV/AIDS would have dramatic positive consequence for the course and access of HIV/AIDS and particularly pertinent for substance abusers and in resource limited settings.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA028555-03
Application #
8378255
Study Section
Special Emphasis Panel (ZRG1-AARR-D)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$212,123
Indirect Cost
$69,278
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Heinrichs-Graham, Elizabeth; Santamaria, Pamela M; Gendelman, Howard E et al. (2017) The cortical signature of symptom laterality in Parkinson's disease. Neuroimage Clin 14:433-440
Kevadiya, Bhavesh D; Bade, Aditya N; Woldstad, Christopher et al. (2017) Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomater 49:507-520
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Gnanadhas, Divya Prakash; Dash, Prasanta K; Sillman, Brady et al. (2017) Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest 127:857-873
Shahnaz, Gul; Edagwa, Benson J; McMillan, JoEllyn et al. (2017) Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond) 12:99-115
Gendelman, Howard E (2017) Thank You! J Neuroimmune Pharmacol 12:565
Embury, Christine M; Dyavarshetty, Bhagyalaxmi; Lu, Yaman et al. (2017) Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease. J Neuroimmune Pharmacol 12:340-352
Bade, Aditya N; Gendelman, Howard E; Boska, Michael D et al. (2017) MEMRI is a biomarker defining nicotine-specific neuronal responses in subregions of the rodent brain. Am J Transl Res 9:601-610
Edagwa, Benson; McMillan, JoEllyn; Sillman, Brady et al. (2017) Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv 14:1281-1291

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