Durham Research Center 3051
985800 Nebraska Medical Center
Omaha, NE 68198-5800
E-mail: JoEllyn McMillan
Keywords: toxicology, environmental, genomics, toxicity mechanisms nanomedicine, drug analysis, cell cultures, antiretroviral drugs, anti-cancer drugs, anti-inflammatory drugs, antimalarial drugs, hemolytic anemia
My research interests and training have been in the field of toxicology. Past research areas have involved the use of cell and whole animal models to study mechanisms of liver toxicity of drugs and environmental chemicals.
My present research interests lie in developing nanoformulations of antiretroviral drugs and testing these in cell-based and animal model systems. In collaboration with Dr. Howard Gendelman, we are developing long-acting nanoformulations of antiretroviral drugs for targeted and cell-based drug delivery for treatment of HIV-1 infection. The development of long-acting nanoformulations of antiretroviral drugs would simplify drug dosing regimens, extend dosing intervals, reduce unwanted drug side effects, and improve drug penetration into viral sanctuary sites, thus reducing development of drug resistance. These nanoformulations can be specifically targeted to cells by coating them with targeting moieties for specific cell receptors. By targeting mononuclear phagocytes, we hope to use these cells as vehicles for delivery of drug to sites that are normally inaccessible to antiretroviral drugs, specifically the brain and lymph nodes. These cells can also serve as storage sites for the nanoformulated drugs, providing steady release of drug(s) over an extended period of time and hence reducing drug doses and extending drug-dosing intervals. Our drug nanoformulations are first screened in macrophage-based assays for cell uptake, retention, release and efficacy against HIV-1 infection. Select nanoformulations are then tested in animal models for pharmacokinetics, biodistribution, and efficacy against HIV-1 infection. To determine antiretroviral efficacy in mice, immune deficient mouse models reconstituted with human immune cells are used. These mice have been developed in the laboratories of Dr. Larisa Poluektova and Dr. Santhi Gorantla. Large animal pharmacokinetics of select nanoformulations are being determined in collaboration with Dr. Howard Fox’s laboratory. These studies are in anticipation of conducting preclinical safety assessment studies of specific antiretroviral drug nanoformulations that can be advanced to Phase I clinical trials.
- Nowacek AS, Balkundi S, McMillan J, Roy U, Martinez-Skinner A, Mosley RL, Kanmogne G, Kabanov AV, Bronich T, Gendelman HE. Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages. J. Controlled Rel, 150: 204-211, 2011. PMID: 21108978
- Kadiu I, Nowacek A, McMillan J, Gendelman HE. Macrophage endocytic trafficking of antiretroviral nanoparticles. Nanomedicine, 6: 975-994, 2011.PMID: 21417829
- Balkundi, S, Nowacek, AS, Veerubhotla, RS, Chen, H, Martinez-Skinner, A, Roy, U, Mosley, RL, Kanmogne, G, Liu, X, Kabanov, AV, Bronich T, McMillan J, Gendelman, HE. Comparative manufacture and cell-based delivery of antiretroviral nanoformulations. Int. J. Nanomedicine. 6: 3393-3404, 2011. PMID: 22267924
- Roy U, McMillan J, Alnouti Y, Gautum N, Smith N, Balkundi S, Dash P, Gorantla S, Martinez-Skinner A, Meza J, Kanmogne G, Swindells S, Cohen S, Mosley RL, Poluektova L, Gendelman HE. Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human PBL-reconstituted mice. J. Infect. Dis. 2012, 206:1577-1588.PMID: 22811299
- Dash PK, Gendelman HE, Roy U, Balkundi S, Alnouti Y, Mosley RL, Gelbard HA, McMillan J, Gorantla S, Poluektova LY. Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1 infected humanized mice. AIDS. 2012, 26:2135-2144. PMID: 22824628
- Gautam N, Roy U, Balkundi S, Puligujja P, Guo D, Smith N, Liu X, Lamberty B, Morsey B, Fox H, McMillan J, Gendelman HE, Alnouti Y. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob. Agents Chemother., 206: 1577-1588, 2013. PMID: 23612193
- Puligujja P, McMillan J, Kendrick L, Li T, Balkundi S, Smith N, Veerubhotla RS, Kabanov A, Bronich T, Gendelman HE, Liu X. Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution aiding in the elimination of human immunodeficiency virus infection. Nanomedicine: Nanotech. Biol. Med., 9(8):1263-73, 2013. PMID: 23680933
- Edagwa BJ, Zhou T, McMillan JM, Liu XM, Gendelman HE. Nanomedicine for the Viral Reservoir Drug Delivery and the Fight Against HIV Infection. Curr Med Chem. 2014 Aug 26. PMID: 25174930
- Guo D, Zhang G, Wysocki TA, Wysocki BJ, Gelbard HA, Liu XM, McMillan JM, Gendelman HE. Endosomal trafficking of nanoformulated antiretroviral therapy facilitates drug particle carriage and HIV clearance. J Virol. 88(17):9504-13. 2014. PMID: 24920821
- Singh D, McMillan JM, Liu XM, Vishwasrao HM, Kabanov AV, Sokolsky-Papkov M, Gendelman HE. Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues. Nanomedicine 9(3):469-85, 2014. PMID: 24646020
Additional publications in PubMed.