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

Award Number: R21AA029750
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $226,406 )
2023	2023	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE	KINGSTON	RI	02881	WASHINGTON	USA	Alcohol Research Programs	000	2	2/24/2023	NON-COMPETING CONTINUATION	$226,406
														Subtotal = $226,406

Issue Date FY: 2022 ( Subtotal = $187,031 )
2022	2022	UNIVERSITY OF RHODE ISLAND	75 LOWER COLLEGE	KINGSTON	RI	02881	WASHINGTON	USA	Alcohol Research Programs	000	1	3/17/2022	NEW	$187,031
														Subtotal = $187,031

Grand Total All Awards = $413,437

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

Award Number: R21AA029750

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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