This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into long acting scalable medicines. A tripartite approach is offered. The first is the conversion of ?partially? hydrophobic ARVs into lipophilic prodrug crystals encased in polymers for efficient transfer across cell and tissue barriers. The second is deployment of mononuclear phagocyte (MP; monocyte, macrophage and dendritic cells) as drug depots by housing the crystalline ARV particles into autophagosomes and releasing drug inside the cell through hydrolysis. The third decorates the particles with ligands serving to facilitate entry into cell and tissue lymphoid viral reservoirs. The overarching goal is to make long-acting slow effective release antiretroviral therapy (LASER ART) with dosing intervals of once every six months in order to maximize the effectiveness of any treatment or pre-exposure prophylaxis regimen. Complete control of viral replication in the central nervous system, lymph nodes and gut associated lymphoid tissues is the desired endpoint. To accomplish this multidisciplinary research, a partnership was forged between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist and immunologist (H Gendelman). This merger will continue to speed the transformation of short to long acting ARVs (for example entry, nucleoside and nonnucleoside reverse transcriptase and integrase inhibitors) in combination therapy. Biological testing will follow product development in relevant cell and animal models of human disease. Formulation safety will be realized by first testing replicate short acting ARV formulations. The pathway for drug/nanocrystal development will move forward by a series of now carefully crafted Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting, toxicology, pharmacokinetics and pharmacodynamics (PD) profiles follow a carefully organized and safe action plan based on drug performance. Several have ?reached? nonhuman primates through drug manufacture by a now operational good laboratory practice facility. These new LASER ART formulations can be joined with an autophagy medicine to further extend cell drug depots (HA Gelbard). The successful outcome of these experiments can circumvent drug toxicities, improve regimen adherence, provide more crafted viral prevention measures and easily enter viral reservoirs such as the brain. Maximal reduction in residual infection is the project goal. The research builds on an already strong track record in macrophage-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be tested by computation (TA Wysocki). PD screens in humanized mice (S Gorantla) will validate the findings. The overall premise is to develop the necessary ?state of the art? tools to positively transform existing antiretroviral treatment regimens by bench to bedside approaches.
We will convert short acting antiretroviral drugs (ARVs) into long-acting slow effective release ART (LASER ART) with potent activities against the human immunodeficiency virus (HIV). LASER ART is chemically modified ARVs that form hydrophobic and lipophilic drug crystals packaged into nanoparticles. They are made to extend drug-dosing intervals from once/day to once/six months. The generation of decorated ARV nanocrystals are boosted by a second medicine that protects the first from cell destruction serving to improve its delivery to body tissues where HIV grows such as the lymph nodes and gut.
| Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193 |
