# Improved Nanoparticle Targeting of Tissue Myeloid Cells for HIV-1 Long-acting Pre-exposure Prophylaxis

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2024 · $788,992

## Abstract

Summary
Antiretroviral pre-exposure prophylaxis (PrEP) is an important tool for preventing transmission to virus naïve
individuals and plays an important role in current efforts to end the HIV epidemic. If taken daily current oral PrEP
strategies reliably block HIV transmission. However, the requirement of strict adherence to daily pill uptake, pill
fatigue and other institutional barriers to access leave oral PrEP underutilized. Long-acting injectable PrEP
strategies have the potential to address many of the problems associated with oral PrEP but the realization of
drug formulations and delivery strategies that ensure sustained drug release for at least three months has
remained challenging and motivates the development of entirely new long-acting PrEP strategies. This project
develops a long-acting injectable PrEP strategy based on membrane-wrapped nanoparticles (NPs) that establish
cellular depots for sustained maintenance of inhibitory concentrations of antiretrovirals (ARVs) at primary tissue
sites of HIV-1 transmission in the female genital tract (FGT) and rectum. Selective targeting of CD169-expressing
macrophages and dendritic cells is accomplished through incorporation of the ganglioside GM3 in the NP
membrane. GM3-CD169 binding triggers uptake and sequestration of NPs in non-endolysosomal compartments
that share distinct similarities with virus containing compartments (VCCs) in tissue-associated macrophages and
dendritic cells. These compartments represent protected sites from where NPs can release drugs into the
surrounding tissue for an extended period of time. Membrane-wrapped inverse micelles of block copolymers will
be engineered as a GM3-NP platform for long-acting PrEP. A combination of long-acting tenofovir (TFV) and
emtricitabine (FTC) prodrugs will be used as active compounds to validate the approach. The block copolymer
NPs will contain TFV covalently linked to a polymer shell that encapsulates an aqueous core holding FTC
conjugated to dendrimers. After quantifying drug loading and release in vitro, the GM3-mediated targeting of
CD169+ myeloid cells in the FGT and rectum of a humanized mouse model will be tested. In parallel, the GM3-
NP platform will be optimized to achieve sustained drug release in the target tissues. The hypothesis that the
optimized NPs provide protection from mucosal HIV infection in a humanized mouse model for at least three
months will be tested. The specific aims of this application are:
Aim 1: To develop membrane-wrapped multicomponent NPs for sustained release of TFV/FTC.
Aim 2: To target CD169-expressing myeloid cells in the FGT and SLTs for sustained TFV/FTC release.
Aim 3: To demonstrate long-term protection from mucosal HIV-1 transmission in humanized mice by TFV/FTC
incorporating GM3-NPs.

## Key facts

- **NIH application ID:** 10811673
- **Project number:** 5R01AI175068-02
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Zandrea Ambrose
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $788,992
- **Award type:** 5
- **Project period:** 2023-03-17 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811673

## Citation

> US National Institutes of Health, RePORTER application 10811673, Improved Nanoparticle Targeting of Tissue Myeloid Cells for HIV-1 Long-acting Pre-exposure Prophylaxis (5R01AI175068-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10811673. Licensed CC0.

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