# Development of Sustained-Release Anti-HIV Nucleoside Phosphonate Nanoparticles

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $749,444

## Abstract

Project Summary
Despite the remarkable progress in drug development over the past 20 years, antiretroviral treatment success
is not universal. The most frequent cause of treatment failure in both therapeutic and prophylactic settings
continues to be challenges associated with drug adherence. Although many patients can manage daily
adherence for substantial periods of time, treatment fatigue as well as special difficulties exist for vulnerable
patient populations including those challenged by substance abuse, mental illness, prolonged periods away
from home and stigma within their communities. All too often treatment failure ensues. This has led to an
increasing interest in the development of antiretroviral chemotherapeutic agents that can be given at prolonged
dosing intervals. Several novel compounds and compounding approaches have emerged that suggest this
goal is highly attainable. In this application we wish to develop an effective approach to deliver the globally
used nucleotide, tenofovir, to the list of agents that can be administered at monthly intervals.
We have demonstrated that ester linkage of an alkoxyalkyl side chain to the parent molecule greatly enhances
cellular uptake and that we can modify the rate of intracellular release by the addition of a second promoiety at
the remaining phosphonate oxygen. The combined effect of these modifications results in rapid cellular uptake
and sustained “timed-release” delivery of tenofovir diphosphate to the intracellular compartment. One lead
compound, the octadecyloxyethyl benzyl diester of tenofovir (ODE-Bn-TFV), has single nanomolar anti-HIV
activity and a selectivity index of >3000. Tenofovir diphosphate was slowly liberated in the intracellular
compartment where it maintained a half-life of more than a week. We propose to utilize this approach to
develop additional compounds of even greater potency and intracellular half-life. We will compound our novel
time-release molecules in nanoparticles that will slowly release these molecules into the systemic circulation
from the site of intramuscular injection. We believe that by using nanotechnology to first modulate release of
prodrug into the systemic circulation and then using a synthetic chemical approach to enhance cellular uptake
and to slow intracellular decay that we can deliver potent antiviral activity to sites of viral replication for a month
following intramuscular injection.

## Key facts

- **NIH application ID:** 9852960
- **Project number:** 5R01AI131424-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert Turner Schooley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $749,444
- **Award type:** 5
- **Project period:** 2017-02-21 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852960

## Citation

> US National Institutes of Health, RePORTER application 9852960, Development of Sustained-Release Anti-HIV Nucleoside Phosphonate Nanoparticles (5R01AI131424-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852960. Licensed CC0.

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