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
UNMC Today | February 6, 2018
Chemically modified drug shows promise for HIV treatment, elimination
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.
- Sillman B, Bade AN, Dash PK, Bhargavan B, Kocher T, Mathews S, Su H, Kanmogne GD, Poluektova LY, Gorantla S, McMillan J, Gautam N, Alnouti Y, Edagwa B, and Gendelman HE. Creation of a long-acting nanoformulated dolutegravir. Nat. Commun. In Press, 2018.
- Kevadiya BD, Woldstad C, Ottemann BM, Dash P, Sajja BR, Lamberty B, Morsey B, Kocher T, Dutta R, Bade AN, Liu Y, Callen SE, Fox HS, Byrareddy SN, McMillan JM, Bronich TK, Edagwa BJ, Boska MD, and Gendelman HE. Multimodal theranostic nanoformulations permit magnetic resonance bioimaging of antiretroviral drug particle tissue-cell biodistribution. Theranostics, 8:256-76, 2018. PMID: 29290806. PMC5743473.
- McMillan J, Szlachetka A, Slack L, Sillman B, Lamberty B, Morsey B, Callen S, Gautam N, Alnouti Y, Edagwa B, Gendelman HE, and Fox HS. Pharmacokinetics of a long-acting nanoformulated dolutegravir prodrug in rhesus macaques. Antimicrob. Agents Chemother., 62(1), 2018. PMID: 29061742. PMC5740312.
- Zhou T, Su H, Dash P, Lin Z, Dyavar Shetty BL, Kocher T, Szlachetka A, Lamberty B, Fox HS, Poluektova L, Gorantla S, McMillan J, Gautam N, Mosley RL, Alnouti Y, Edagwa B, and Gendelman HE. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials, 151:53-65, 2018. PMID: 29059541.
- Gnanadhas DP, Dash PK, Sillman B, Bade AN, Lin Z, Palandri DL, Gautam N, Alnouti Y, Gelbard HA, McMillan J, Mosley RL, Edagwa B, Gendelman HE, and Gorantla S. Autophagy facilitates macrophage depots of sustained release nanoformulated antiretroviral drugs. J. Clin. Invest. 127(3):857-873, 2017. PMID: 28134625
- Edagwa B, McMillan J, Sillman B, and Gendelman HE. Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv. 6:1-11, 2017. PMID: 28128004
- Kevadiya BD, Bade AN, Woldstad C, Edagwa BJ, McMillan JM, Sajja BR, Boska MD, and Gendelman HE. Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomaterialia. 49:507-520, 2017. PMID: 27916740
- Shahnaz G, Edagwa BJ, McMillan J, Akhtar S, Raza A, Qureshi NA, Yasinzai M, Gendelman HE. Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond). 12(2):99-115, 2017. PMID: 27879160. PMCID: PMC5144491
- Guo D, Zhou T, Arainga M, Palandri D, Gautam N, Bronich T, Alnouti Y, McMillan J, Edagwa B, and Gendelman HE. Creation of a long-acting nanoformulated 2’,3’-dideoxy-3’-thiacytidine. JAIDS, 74(3):e75-e83, 2017. PMID: 27559685. PMCID: PMC5305294
- Singh D, McMillan J, Hilaire J, Gautam N, Palandri D, Alnouti Y, Gendelman HE, and Edagwa B. Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond), 11(15): 1913-1927, 2016. PMID: 27456759
- Martinez-Skinner AL, Araínga MA, Puligujja P, Palandri DL, Baldridge HM, Edagwa BJ, McMillan JM*, Mosley RL, and Gendelman HE. Cellular Responses and Tissue Depots for Nanoformulated Antiretroviral Therapy. 2015; PLoS One, 10(12):e0145966.PMID: 26716700. PMCID: PMC4696780.
- Puligujja P, Arainga M, Dash P, Palandri D, Mosley RL, Gorantla S, Poluektova L, McMillan J, and Gendelman HE. Pharmacodynamics of folic acid-receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice. Antiviral Res., 120: 85-88, 2015. PMID: 26026666.
Additional publications in PubMed.