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.
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.
|Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410|
|Schutt, Charles R; Gendelman, Howard E; Mosley, R Lee (2018) Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson's disease. Mol Neurodegener 13:26|
|Sillman, Brady; Bade, Aditya N; Dash, Prasanta K et al. (2018) Creation of a long-acting nanoformulated dolutegravir. Nat Commun 9:443|
|Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154|
|Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) URMC-099 facilitates amyloid-? clearance in a murine model of Alzheimer's disease. J Neuroinflammation 15:137|
|Kevadiya, Bhavesh D; Woldstad, Christopher; Ottemann, Brendan M et al. (2018) Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics 8:256-276|
|McMillan, JoEllyn; Szlachetka, Adam; Slack, Lara et al. (2018) Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother 62:|
|Sillman, Brady; Woldstad, Christopher; Mcmillan, Joellyn et al. (2018) Neuropathogenesis of human immunodeficiency virus infection. Handb Clin Neurol 152:21-40|
|Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193|
|Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65|
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