Brady Sillman, PhD
Laboratory: Howard E. Gendelman, MD
University of Nebraska Medical Center (DRC 3060)
985800 Nebraska Medical Center
Omaha Nebraska, NE 68198-5800
Keywords: HIV-1, Antiretroviral Therapy (ART), Long-Acting Injectables (LAI), Nanomedicine, Prodrug, LASER ART (long-acting slow effective release antiretroviral therapy), Drug Delivery
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My research is focused on developing long-acting slow effective release antiretroviral therapy (LASER ART), with the goal of a once-a-year injectable formulation, for the treatment of Human Immunodeficiency Virus 1 (HIV-1) infection. To achieve this, we developed novel systems of modifying and nanoformulating ART and targeting it to macrophages in vivo to facilitate drug storage, protection, and delivery to viral reservoirs. Together, these systems (drug modification and formulation) help to prolong the apparent half-life of the drugs, allowing for extended dosing regimens, along with improving the overall pharmacokinetics, biodistribution, and pharmacodynamics of the drugs. My long-term research interests involve the development of a comprehensive understanding of drug design, modification, and delivery and how these contribute to the treatment of human diseases, notably HIV-1.
- Development of a Once-A-Year Long-Acting Injectable Integrase Inhibitor for the Treatment of HIV-1 Infection:
My main research focus is on transforming currently available HIV-1 integrase inhibitors (dolutegravir and cabotegravir) into a once-a-year long-acting injectable for use in pre-exposure prophylaxis (PrEP), HIV-1 transmission control, and maintenance therapy in virologically surpressed patients. Such a long-acting regimen will allow increased patient compliance with an ability to maintain consistent drug levels at effective concentrations in plasma and tissues. This strategy will improve treatment outcomes and could act as a vaccine mimetic. To these ends, I am involved in the synthesis, characterization, and quality control of libraries of prodrugs of these integrase inhibitors. Nanoformulations are then prepared by encasement of the prodrugs in biocompatible surfactants to create lipophilic-hydrophobic nanocrystals. Efficacy and toxicity of these nanocrystals are tested in different in vitro and rodent models. Detailed pharmacokinetic profiles of native antiretroviral drugs and respective long-acting nanoformulations in rodents are assessed. Lead candidates are moved forward to studies in non-human primates, with an eye towards planned human phase I testing.
- Sillman, B., Bade, A.N., Dash, P.K., Bhargavan, B., Kocher, T., Mathews, S., Su, H., Kanmogne, G.D., Poluektova, L.Y., Gorantla, S., McMillan, J., Gautam, N., Alnouti, Y., Edagwa, B., & Gendelman, H.E. (2018): Creation of a Long-Acting Nanoformulated Dolutegravir. Nature Communications, 9(1): 443.
- McMillan, J., Szlachetka, A., Slack, L., Sillman, B., Lamberty, B. Morsey, B., Callen, S., Gautam, N., Alnouti, Y., Edagwa, B., Gendelman, H.E., & Fox, H.S. (2017): Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrobial Agents and Chemotherapy, 62(1).
- Kulkarni, T.A., Bade, A.N., Sillman, B., Dyavar Shetty, B.L., Wojtkiewicz, M.S., Gautam, N., Hilaire, J.R., Sravanam, S., Szlachetka, A., Lamberty, B.G., Morsey, B.M., Fox, H.S., Alnouti, Y., McMillan, J.M., Mosley, R.L., Meza, J., Domanico, P.L., Yue, T.Y., Moore, G., Edagwa, B.J., & Gendelman, H.E. (2020): A Year-Long Extended Release Nanoformulated Cabotegravir Prodrug. Nature Materials, 19(8):910-920.
- Hilaire, J.R., Bade, A.N., Sillman, B., Gautam, N., Herskovitz, J., Dyavar Shetty, B.L., Wojtkiewicz M.S., Szlachetka, A., Lamberty, B.G., Sravanam, S., Fox, H.S., Alnouti, Y., Dash, P.K., McMillan, J.M., Edagwa, B.J., & Gendelman, H.E. (2019): Creation of a Long-Acting Rilpivirine Prodrug Nanoformulation. Journal of Controlled Release, 311-312:201-211.
- Dash, P.K., Kaminski, R., Bella, R., Su, H., Mathews, S., Ahooyi, T.M., Chen, C., Mancuso, P., Sariyer, R., Ferrante, P., Donadoni, M., Robinson, J.A., Sillman, B., Lin, Z., Hilaire, J.R., Banoub, M., Elango, M., Gautam, N., Mosley, R.L., Poluektova, L.Y., McMillan, M., Bade, A.N., Gorantla, S., Sariyer, I.K., Burdo, T.H., Young, W.B., Amini, S., Gordan, J., Jacobson, J.M., Edagwa, B., Khalili, K., & Gendelman, H.E. (2019): Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice. Nature Communications, 10(1): 2753.