# Modulating macrophage function in atherosclerosis by functionalized nanoparticles

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $634,543

## Abstract

Project Summary
Accumulation of cholesteryl esters (CE)-laden macrophage (M) foam cells in the arterial intima is a hallmark
of atherosclerotic plaque development that underlies cardiovascular diseases (CVD). Current therapies are
primarily targeted at reducing the circulating plasma LDL-C levels either by reducing de novo cholesterol
synthesis (by statins) or by reducing absorption of dietary cholesterol (by ezetimibe). However, despite
attaining target plasma LDL-C levels, residual risk due to the burden of existing plaque still remains.
Furthermore, the inherently inflammatory milieu of the plaque contributes to the vulnerability of the plaque that
leads to acute events such as heart attacks and stroke. Recent advances have established the critical role of
inadequate removal of cholesterol from the plaques and defective removal of apoptotic cells from the
advancing plaques (i.e., reduced efferocytosis) as two very critical mechanisms for intra-plaque inflammation
and vulnerability. Therefore, the long-term goal of this project is to develop novel strategies to effectively
decrease the CE burden of existing plaques as well as to reduce plaque inflammation. Earlier studies from the
PI's (Ghosh) laboratory have demonstrated that targeted reduction in M CE accumulation not only reduced
cholesterol content and size of the plaque but it also significantly reduced plaque associated inflammation
resulting in reduced M apoptosis and necrosis. It is also noteworthy that in contrast to directly targeting
reduction in plaque inflammation using anti-inflammatory agents that will modulate only one risk factor, indirect
modulation by reducing cellular cholesterol content achieves reduction of two critical risk factors, namely, CE
levels as well as inflammation. However, one of the biggest challenges in such targeted modulation
approaches is the availability of appropriate delivery platforms. Nanomedicines provide such a platform and
working in close collaboration, the two PIs of this multi-PI proposal have developed mannose-functionalized
polyamidoamine (PAMAM) dendrimer based nanoparticles (DNPs) to deliver agents characterized to
beneficially modulate cellular functions specifically to M via the mannose receptor and demonstrated in vivo
efficacy in reducing atherosclerotic plaque burden/inflammation. We hypothesize that “development of
functionalized nanoparticles with an increased potential for uptake by macrophages and delivery of
agents to enhance CE removal as well as modulate inflammation will facilitate or enhance the
beneficial modulation of macrophage function.” This hypothesis will be tested by the following two Aims:
Aim 1: Using a functionalized DNP platform, deliver agent(s) to enhance cholesterol mobilization from M
foam cells and simultaneously reduce plaque-associated inflammation. Aim 2: To establish the ability of
functionalized DNPs to deliver enhancers of efferocytosis and effectively modulate this specific function of
Ms. The succ...

## Key facts

- **NIH application ID:** 9959462
- **Project number:** 5R01HL140684-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** SHOBHA GHOSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $634,543
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959462

## Citation

> US National Institutes of Health, RePORTER application 9959462, Modulating macrophage function in atherosclerosis by functionalized nanoparticles (5R01HL140684-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9959462. Licensed CC0.

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