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Principal Investigator: Jyothi Unnikrishna Menon
Organization: UNIVERSITY OF RHODE ISLAND
Fiscal Year: 2024
Award: $406,851
Funding agency: National Cancer Institute
ABSTRACT
Hepatocellular carcinoma (HCC), the fastest rising cause of cancer-related deaths worldwide with a 5-year
survival of <20%, affects more than 41,000 individuals in the United States every year. Heavy alcohol
consumption leading to fatty liver, hepatitis and cirrhosis has been identified as a key risk factor in HCC
development. Current therapies against alcohol liver disease (ALD) and associated fibrosis are non-specific and
ineffective. Alcohol abstinence remains the gold standard for ALD treatment to prevent progression to HCC,
however this is often hampered by poor compliance. The goal of this proposal is to develop a novel
multifunctional nanoparticle (NP) platform (lipid-PLGA NPs) for treatment of alcohol-associated fibrosis via
targeted activation of G-protein-coupled bile acid receptor (Gpbar1) and anti-fibrotic drug delivery. The NPs will
also release collagenase to facilitate greater NP penetration into the fibrotic liver tissue. We hypothesize that (i)
NP-mediated targeted activation of Gpbar1 – a membrane protein expressed in Kupffer cells (KCs) and not
hepatocytes, will suppress NF-kβ and STAT3 signaling responsible for HCC development, and (ii) targeted
Gpbar1 activation and concurrent anti-fibrotic drug release will synergistically inhibit profibrotic biomarker
expressions and cytokine signaling, leading to attenuation of fibrosis. Preliminary investigations by our
collaborative research team confirmed that the NPs can selectively accumulate in the KCs in in vivo mouse
models. Our proposed aims are: (1) Characterization and in vitro evaluation of liver tissue penetration properties
of the collagenase-containing lipid-PLGA NPs. Physicochemical characterization will be done to ensure that the
lipid-PLGA NPs will have optimal properties for accumulation in the liver. A 3D multicellular spheroid model of
alcohol-induced liver fibrosis will be used to evaluate cytocompatibility, optimum uptake concentrations, and
tissue penetration by the NPs in vitro. (2) Gpbar1 agonist incorporation and in vivo elucidation of safety,
biodistribution and Gpbar1 targeting capabilities of the NPs. Gpbar1 targeting, safety and anti-fibrotic effects of
the lipid-PLGA NPs will be investigated using a widely studied and reported carbon tetrachloride-plus-alcohol
induced mouse models of liver fibrosis. (3) In vitro and in vivo evaluation of synergistic effects of Gpbar1-targeting
lipid-PLGA NPs given in combination with anti-fibrotic therapies. In this aim, the synergistic effects of Gpbar1
activation and interleukin-17A signaling inhibition on fibrosis attenuation will be determined following
encapsulation of anti-fibrotic therapies within the lipid-PLGA NPs. NP efficacy will be evaluated using histology,
biomarker analysis and collagen assays. As a first step towards assessing the translational potential of the
formulation, we will then investigate the therapeutic effects of the NPs using novel ALD liver fibrosis-on-a-chip
developed using primary murine cells. This innovative project will lead to a paradigm shift in the development
and testing of new therapeutic strategies against chronic liver diseases to prevent their progression to HCC.
Terms: <3-D><3-Dimensional><3D><ATRA><Accounting><Adverse effects><Affect><Agonist><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcoholic Liver Diseases><Alcohols><Assay><Attenuated><Bile Acids><Bile Duct Obstruction><Biliary Stasis><Bioassay><Biodistribution><Biological Assay><Biological Markers><Body Tissues><Cancer Cause><Cancer Etiology><Cancers><Carbon Tetrachloride><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Spheroids><Cessation of life><Charge><Cholestasis><Chronic><Cirrhosis><Clinic><Clinical><Collaborations><Collagen><Collagen Peptidase><Collagen-Degrading Enzyme><Combined Modality Therapy><Coupled><Cytokine Signal Transduction><Cytokine Signaling><Data><Death><Deposit><Deposition><Development><Diameter><Disease><Disease Progression><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><Dysfunction><Encapsulated><EtOH abuse><EtOH drinking><EtOH use><Evaluation><Exploratory/Developmental Grant for Diagnostic Cancer Imaging><Fatty Liver><Fibrosis><Formulation><Functional disorder><G alpha13 Protein><G(13) Protein><G-Proteins><G13 G-Protein><G13 Protein><G13 Subunit G-Protein><GTP-Binding Proteins><GTP-Regulatory Proteins><Galpha13 Protein><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Hepatic><Hepatic Disorder><Hepatitis><Hepatocarcinogenesis><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Histology><Human><In Vitro><In vivo analysis><Individual><Inflammation><Inflammatory><Injury><Injury to Liver><Interleukins><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous><Investigation><Kupffer Cells><Ligands><Lipids><Liver><Liver Carcinogenesis><Liver Cells Carcinoma><Liver Fibrosis><Liver Steatosis><Liver diseases><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Modern Man><Molecular Target><Multicellular Spheroids><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NIH><National Institutes of Health><Outcome><Pathway interactions><Penetration><Pharmaceutical Preparations><Physiopathology><Polymers><Position><Positioning Attribute><Primary carcinoma of the liver cells><Production><Property><R21 Award><Receptor Activation><Receptor Protein><Reporting><Reproducibility><Research><Retinoic Acid><Rhode Island><Risk Factors><STAT3><STAT3 gene><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Stellate Sinusoidal Macrophage><Surface><Surface Proteins><Testing><Tetrachloromethane><Therapeutic><Therapeutic Effect><Therapeutic Studies><Therapy Research><Tissues><Trans Vitamin A Acid><Tretinoin><Tretinoinum><United States><United States National Institutes of Health><Universities><Validation><Vitamin A Acid><Work><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><alcohol abstinence><alcohol abuse therapy><alcohol abuse treatment><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol prevention><alcohol problem><alcohol product use><alcohol related liver disease><alcohol treatment><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><all-trans-Retinoic Acid><all-trans-Vitamin A acid><antifibrotic agent><antifibrotic medication><antifibrotic therapy><antifibrotic treatment><attenuate><attenuates><attenuation><bile obstruction><bile occlusion><bio-markers><biologic marker><biological signal transduction><biomarker><cancer type><carcinogenesis in the liver><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><chronic EtOH drinking><chronic alcohol consumption><chronic alcohol drinking><chronic alcohol ingestion><chronic alcohol use><chronic ethanol consumption><chronic ethanol drinking><chronic ethanol ingestion><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><chronic liver injury><cirrhotic><collagenase><combination therapy><combined modality treatment><combined treatment><cytokine><design><designing><developmental><drug/agent><effective therapy><effective treatment><ethanol abstinence><ethanol abuse><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><fibrotic liver><hazardous alcohol use><hepatic body system><hepatic carcinogenesis><hepatic damage><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic injury><hepatic organ system><hepatic steatosis><hepatocellular carcinogenesis><hepatopathy><hepatosteatosis><improved><in vivo><in vivo evaluation><in vivo testing><inflamed liver><inhibitor><injuries><innovate><innovation><innovative><interventional strategy><liver cancer pathogenesis><liver carcinoma><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><liver tumorigenesis><malignancy><mortality><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano particle><nano particle delivery><nano polymer><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanopolymer><nanosized particle><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathophysiology><pathway><polymer><polymeric><pre-clinical assessment><preclinical assessment><prevent><prevent alcohol><preventing><preventing alcohol><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><receptor><small molecule><tetrachloro-methane><three dimensional><trans-Retinoic Acid><translational opportunities><translational potential><uptake><validations>