Durham Research Center 3064
985800 Nebraska Medical Center
Omaha, NE 68198-5800
Keywords: HIV-1, tuberculosis, medicinal chemistry, polymer chemistry, drug delivery, theranostics, LASER ART (long acting slow effective release antiretroviral therapy)
Chemically modified drug out of UNMC could hasten an HIV cure
Julie Anderson, Omaha World-Herald | February 10, 2018
Chemically modified drug shows promise for HIV treatment, elimination
UNMC Today | February 6, 2018
To ensure efficacy, conventional antiretroviral therapies (ART) require frequent administration to maintain plasma and tissue drug concentrations in the therapeutic range. ART’s failure to eliminate HIV-1 at sites of restricted infection underpins its limitations. ART’s half-life, tissue biodistribution and maintenance of optimal therapeutic drug levels at anatomical sites could be realized through cell and tissue targeted long acting slow effective delivery systems and by optimizing drug metabolism. My research interests are in the areas of design, development and evaluation of antiretroviral prodrugs, development of long acting slow effective release ART (LASER ART) and their application to testing in cell and small animal based assays. In collaboration with Dr. Howard Gendelman and members of the nanomedicine laboratory at UNMC, we have demonstrated that both hydrophilic and hydrophobic therapeutic compounds could be converted into LASER ART. Single administration of LASER ART significantly extends the half-life of therapeutic compounds. The LASER ART are developed through novel chemistry strategies coupled with autophagy stimulation to sustain cell and tissue ART depots.
One of our research goals is to translate existing antiretroviral drugs (ARVs) into long acting compounds. We are focused on making a library of LASER ART targeting multiple phases of the viral life cycle to limit viral resistance while improving patient compliance. ARVs are first converted into hydrophobic and lipophilic prodrug nanocrystals for efficient transfer across cell and tissue barriers. Targeting ligands are covalently linked to the surface of LASER ART particles to facilitate entry into cell and tissue reservoirs of infection. LASER ART maximizes drug-loading capacity by holding excipient content to a minimum. A range of immune and intracellular LASER ART depot boosters serve to enhance viral clearance. The ultimate goal of this work is to make LASER ART regimen with once-monthly or longer dosing intervals for treatment and prevention of HIV-1.
Another area of interest is the development of theranostic nanoparticles for rapid screening of targeting ligands and non-invasive assessment of LASER ART biodistribution by magnetic resonance imaging (MRI).LASER ART and theranostic nanoparticle sizes are in the same range and both encapsulate hydrophobic and lipophilic ART compounds.
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- 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, Gendelman HE. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018 Jan;151:53-65. PMID: 29059541
- McMillan J, Szlachetka A, Slack L, Sillman B, Lamberty B, Morsey B, Callen S, Gautam N, Alnouti Y, Edagwa B, Gendelman HE, Fox HS. Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother. 2017 Dec 21;62(1). PMID: 29061742. PMCID: PMC5740312
- Edagwa B*, McMillan J, Sillman B, Gendelman HE*. Long-acting slow effective release antiretroviral therapy. Expert Opin. Drug Deliv.2017 Nov;14(11):1281-1291. PubMed PMID: 28128004. PubMed Central PMCID: PMC5545165 (*corresponding authors)
- McMillan J, Szlachetka A, Slack L, Sillman B, Lamberty B, Morsey B, Callen S, Gautam N, Alnouti Y, Edagwa B, Gendelman HE, and Fox H. Pharmacokinetics of a long-acting nanoformulated dolutegravir prodrug in rhesus macaques. Antimicrob. Agents Chemother (in revision)
- 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. 2017. PMID: 28134625; PubMed Central PMCID: PMC5330738
- Kevadiya BD, Bade AN, Woldstad C, Edagwa BJ, McMillan JM, Sajja BR, Boska MD, Gendelman HE. Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging. Acta Biomater 2016. PubMed PMID: 27916740. PubMed Central PMCID: PMC5501313
- Araínga M, Edagwa B, Mosley RL, Poluektova LY, Gorantla S, Gendelman HE. A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14, 17 (2017). PubMed PMID: 28279181. PubMed Central PMCID: PMC5345240
- Singh D, McMillan J, Hilaire J, Gautam N, Palandri D, Alnouti Y, Gendelman HE, Edagwa B. Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond). 2016 Jul 26; PubMed PMID: 27456759. PubMed Central PMCID: PMC4996153
- Guo D, Zhou T, Araínga M, Palandri D, Gautam N, Bronich T, Alnouti Y, McMillan J, Edagwa B*, Gendelman HE*. Creation of a Long Acting Nanoformulated 2’,3’-dideoxy-3’-Thiacytidine. J Acquir Immune Def. 2016 Aug 24; PubMed PMID: 27559685. PubMed Central PMCID: PMC5305294 (* corresponding authors)
- Shahnaz G, Edagwa BJ*, McMillan JM, Akhtar S, Qureshi NA, Yasinzai M, Gendelman HE. Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis. Nanomedicine (Lond). 2017 Jan 12(2):99-115 PubMed PMID: 27879160. PubMed Central PMCID: PMC5144491 (*Corresponding author)
- Edagwa BJ, Zhou T, McMillan JM, Liu XM, Gendelman HE. Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem. 2014;21(36):4186-98. PubMed PMID: 25174930; PubMed Central PMCID: PMC4281174
- Edagwa BJ, Guo D, Puligujja P, Chen H, McMillan J, Liu X, Gendelman HE, Narayanasamy P. Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes. FASEB J. 2014 Dec;28(12):5071-82. PubMed PMID: 25122556; PubMed Central PMCID: PMC4232285