# Prodrug Formulations Create Sustained Release Antiretrovirals

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $747,921

## Abstract

Abstract
This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into scalable long acting medicines.
A step-wise approach is offered with defined “go no go” criteria. The first is conversion of nucleoside reverse
transcriptase and an integrase inhibitor(s) into lipophilic prodrug nanocrystals. These conversions are designed
for simple, safe and scalable productions under current good manufacturing practices. Following the
production of ARV nanocrystals, the second step will optimize CD4+ T cell uptake while sustaining drug
depots in macrophages. ARV release from prodrugs will occur by controlled hydrolysis enabling sustained
antiretroviral potency. The third will facilitate distribution of prodrug nanocrystals into lymphoid, gut associated
lymphoid tissue, genitourinary and central nervous system tissues. The fourth, will complete tests designed to
limit off target toxicity (S Cohen) by screening pro-, native- and nanocrystal- drug formulations in cell and
tissue assays. These extended toxicology tests will serves to investigate any or no adverse events that follow
increased ARV levels in cells and tissues. Our goal is the production of safe well-tolerated long acting slow
effective release antiretroviral therapies with “putative” dosing intervals of up to once every six months. The
design will offer maximal effectiveness for pre-exposure prophylaxis and treatment regimens. The specific aims
are supported by extensive published data sets. To accomplish the proposed research, a partnership was
made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist
(H Gendelman). This collaboration will accelerate transformation of short- to long-acting ARVs. Biological
testing will follow product development in cell and animal models. Formulation safety will be realized by
continuous testing of replicate short-acting native ARV formulations in good laboratory and current good
manufacturing practice facilities. The pathway for ARV nanocrystal development will move forward by
sequential Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting,
toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) profiles follow the action plan. Several have
“reached” drug manufacture. The outcome of these experiments can reduce drug toxicities, improve regimen
adherence, and provide enhanced viral prevention into tissue reservoirs. The research builds on an already
strong track record in cell-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be
tested. PK and PD mouse screens (S Gorantla) will validate the findings. Overall, our long-term goal is to
transform existing antiretroviral treatment regimens into long acting therapies.

## Key facts

- **NIH application ID:** 9955202
- **Project number:** 5R01AI145542-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Benson Edagwa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $747,921
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955202

## Citation

> US National Institutes of Health, RePORTER application 9955202, Prodrug Formulations Create Sustained Release Antiretrovirals (5R01AI145542-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9955202. Licensed CC0.

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