# Nanoparticle-mediated targeting of hepatic macrophages to mitigate inflammation in alcoholic liver disease

> **NIH NIH R21** · UNIVERSITY OF RHODE ISLAND · 2022 · $187,031

## Abstract

ABSTRACT
Chronic and unresolved liver inflammation due to persistent liver injury from alcohol abuse can lead to fibrosis,
cirrhosis and eventually hepatocellular carcinoma (HCC) – which is the fasted growing cause of cancer-related
mortality in the world. Nearly 4.5 million adults in the United States are living with chronic liver disease. Effective
and safe treatment strategies against hepatic inflammation remains an unmet clinical need due to the poor
pharmacokinetics, toxicity and lack of specificity of current therapies. Nanoparticle (NP)-mediated targeted drug
delivery can achieve high hepatic concentrations and low systemic concentrations of the drug. We have
demonstrated that NPs can be targeted towards G-protein coupled bile acid receptor1 (Gpbar1) expressed by
Kupffer cells, to regulate the hepatic inflammatory response. Coating the NPs with pH-responsive polymers
offers further control over the drug release kinetics by facilitating release of the encapsulated drugs into the
acidic inflammatory microenvironment. Therefore, the overarching goal of this R21 project is to develop a Kupffer
cell-targeting dual-functional NP formulation that can be used for targeted stimulation of Gpbar1 and
simultaneous pH-responsive release of anti-inflammatory therapeutics. We hypothesize that the combined action
of Gpbar1 stimulation and anti-inflammatory therapy will have an additive effect in mitigating chronic liver
inflammation associated with alcoholic liver disease. Our proposed aims are: Aim 1: To evaluate the in vivo
targeting capabilities and biodistribution of the Gpbar1-targeted NPs. We will study and optimize the targeting
capabilities and biodistribution of our biodegradable polymeric NPs surface decorated with INT-777- a potent
Gpbar1 agonist, using a widely used chronic-plus-binge animal model of alcoholic liver disease. Aim 2: To
investigate the therapeutic efficacy of the designed NPs in vitro and in vivo. Based on the optimized properties
in Aim 1, the NPs will be further modified to incorporate the anti-inflammatory drug dexamethasone, and tested
against alcohol-treated liver-chip models and the chronic-plus-binge animal models to determine their
pharmacokinetic and pharmacodynamic (PK/PD) properties. We will use histology, biomarker analysis, collagen
assays and cytokine ELISA to study whether our dual-functional NPs can significantly mitigate chronic hepatic
inflammation compared to free drugs or NPs without INT-777. Our results will lead to a paradigm shift in the
development and testing of new therapeutic strategies for chronic liver inflammation, where there is an urgent
need for the development and safe and consistently effective therapies.

## Key facts

- **NIH application ID:** 10352578
- **Project number:** 1R21AA029750-01
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Jyothi Unnikrishna Menon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,031
- **Award type:** 1
- **Project period:** 2022-03-20 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352578

## Citation

> US National Institutes of Health, RePORTER application 10352578, Nanoparticle-mediated targeting of hepatic macrophages to mitigate inflammation in alcoholic liver disease (1R21AA029750-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10352578. Licensed CC0.

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