While antiretroviral therapy (ART) leads to improved morbidity and reduced mortality for HlV-1 infected people, a major limitation rests in the need for lifelong daily regimens. Suboptimal adherence causes increased risk of treatment failure. Drug abuse disorders correlate with such sporadic adherences commonly resulting in accelerated HIV disease progression. Moreover, providers are often reluctant to prescribe ART to patients who abuse or are addicted to drugs because of concerns about the promotion of virologic resistance. Complicating matters further include common cognitive and motor disorders. These risk factors often result in poor treatment outcomes. The advent of slow release ART (ritonavir, indinavir, efavirenz, atazanovir and efavirenz) will positively impact these concerns. Thus, we propose to develop antiretroviral nanoparticles (nanoART) that are carried within circulating immunocytes and delivered to virus-target tissues. Cell-based nanoART theoretically would travel to sites of inflammation and release drug(s) slowly with limited tissue toxicities. Such a drug delivery system, if realized, can revolutionize ART treatment outcomes particularly those within the nervous system. This proposal builds on prior works conducted between our laboratories (Project 1 and 2, A. Kabanov and H. Gendelman). Preliminary investigations demonstrated "proof of concept" in that a single intravenous dose of the nanoART can elicit high-sustained tissue and plasma drug levels in the reticuloendothelial system and brain. NanoART can be taken up within minutes by circulating monocytes and released in tissues over a period of two weeks. Our partners in the University of Nebraska Medical Center College of Pharmacy (Project 1. A. Kabanov and Core C, C Fletcher) will be joined with our College of Medicine Departments of Radiology, Medicine, and Pharmacology and Experimental Neuroscience (Projects 2 and 3 and Core B, H. Gendelman, H. Fox, and M. Boska) to optimize nanoformulations for future human clinical use. This can now be facilitated through integrated cell biologic, pharmacologic, virologic, and molecular testing facilities within UNMC to move an "idea" from the laboratory bench through its translation to the bedside. First, nanoART will be manufactured then optimized in laboratory models of HIV infection. Second, the nanoART will be scaled for testing drug pharmacokinetics in rodents and rhesus macaques. Third, animal studies will be performed in virus-infected rhesus macaques infected with recombinant lentivirus hybrids of SIV and HIV (SHIV) for safety and efficacy investigations, respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA028555-04
Application #
8461286
Study Section
Special Emphasis Panel (ZRG1-AARR-D (40))
Program Officer
Rapaka, Rao
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$1,498,944
Indirect Cost
$489,554
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Kelso, Matthew L; Elliott, Bret R; Haverland, Nicole A et al. (2015) Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J Neuroimmunol 278:162-73
Gendelman, Howard E; Gelbard, Harris A (2014) Adjunctive and long-acting nanoformulated antiretroviral therapies for HIV-associated neurocognitive disorders. Curr Opin HIV AIDS 9:585-90
Guo, Dongwei; Li, Tianyuzi; McMillan, JoEllyn et al. (2014) Small magnetite antiretroviral therapeutic nanoparticle probes for MRI of drug biodistribution. Nanomedicine (Lond) 9:1341-52
Singh, Dhirender; McMillan, JoEllyn M; Liu, Xin-Ming et al. (2014) Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues. Nanomedicine (Lond) 9:469-85
Singh, Dhirender; McMillan, JoEllyn M; Kabanov, Alexander V et al. (2014) Bench-to-bedside translation of magnetic nanoparticles. Nanomedicine (Lond) 9:501-16
Edagwa, Benson J; Zhou, Tian; McMillan, JoEllyn M et al. (2014) Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem 21:4186-98
Gautam, Nagsen; Puligujja, Pavan; Balkundi, Shantanu et al. (2014) Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral nanoformulations. Antimicrob Agents Chemother 58:7510-9
Ivanisevic, Julijana; Epstein, Adrian A; Kurczy, Michael E et al. (2014) Brain region mapping using global metabolomics. Chem Biol 21:1575-84
Gendelman, Howard E; Balogh, Lajos P; Bawa, Raj et al. (2014) The 4th Annual Meeting of the American Society for Nanomedicine. J Neuroimmune Pharmacol 9 Suppl 1:S1-3
Guo, Dongwei; Zhang, Gang; Wysocki, Tadeusz A et al. (2014) Endosomal trafficking of nanoformulated antiretroviral therapy facilitates drug particle carriage and HIV clearance. J Virol 88:9504-13

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