Multifunctional Nanoparticle Platform to Prevent Alcohol-Associated HCC Development

多功能纳米颗粒平台可预防酒精相关的 HCC 发展

基本信息

批准号：
10736984
负责人：
Jyothi Unnikrishna Menon
金额：
$ 28.74万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-03 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736984
关键词：
3-Dimensional Accounting Adverse effects Affect Agonist Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Attenuated Bile Acids Biodistribution Biological Assay Biological Markers Cancer Etiology Carbon Tetrachloride Cells Cellular Spheroids Cessation of life Charge Cholestasis Chronic Cirrhosis Clinic Clinical Collaborations Collagen Combined Modality Therapy Coupled Cytokine Signaling Data Deposition Development Diameter Disease Disease Progression Drug Delivery Systems Encapsulated Evaluation Exploratory/Developmental Grant for Diagnostic Cancer Imaging Fatty Liver Fibrosis Formulation Functional disorder G13 Protein GTP-Binding Proteins Goals Hepatic Hepatitis Hepatocarcinogenesis Histology Human In Vitro Individual Inflammation Inflammatory Injury Interleukins Intervention Intravenous Investigation Kupffer Cells Ligands Lipids Liver Liver Fibrosis Liver diseases Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Proteins Modeling Molecular Target Mus Outcome Pathway interactions Penetration Pharmaceutical Preparations Polymers Positioning Attribute Primary carcinoma of the liver cells Production Property Receptor Activation Reporting Reproducibility Research Rhode Island Risk Factors STAT3 gene Safety Signal Transduction Specificity Surface Testing Therapeutic Therapeutic Effect Therapeutic Studies Tissues Tretinoin United States United States National Institutes of Health Universities Validation Work alcohol abstinence alcohol abuse therapy alcohol prevention antifibrotic treatment attenuation cancer type chronic alcohol ingestion chronic liver disease chronic liver injury collagenase cytokine design effective therapy improved in vivo in vivo evaluation inhibitor innovation liver inflammation liver injury mortality mouse model nanoparticle nanoparticle delivery nanopolymer novel novel therapeutic intervention novel therapeutics pre-clinical assessment prevent receptor small molecule translational potential uptake

项目摘要

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.

抽象的肝细胞癌（HCC），这是全球癌症相关死亡的最快崛起，五年 <20％的生存率每年影响41,000多人。大量酒精导致脂肪肝，肝炎和肝硬化的食用已被确定为HCC的关键危险因素发展。目前针对酒精肝病（ALD）和相关纤维化的疗法是非特异性的，无效。戒酒仍然是ALD治疗的黄金标准，以防止发展为HCC，但是，这通常受到差的依从性的阻碍。该提议的目的是开发小说多功能纳米颗粒（NP）平台（脂质 - Plga NP），用于通过酒精相关的纤维化治疗 G蛋白偶联的胆汁酸受体（GPBAR1）和抗纤维化药物的靶向激活。 NP会我们假设（i） NP介导的GPBAR1的靶向激活 - 在库普弗细胞（KCS）中表达的膜蛋白，而不是肝细胞将抑制负责HCC发育的NF-Kβ和STAT3信号传导，（ii）针对性 GPBAR1激活和并发抗纤维化药物释放将协同抑制纤维化生物标志物表达和细胞因子信号传导，导致纤维化的衰减。我们的初步调查协作研究小组确认，NP可以在体内鼠标中有选择地积累KCS 型号。我们提出的目的是：（1）对肝组织穿透性特性的表征和体外评估含胶原酶的脂质PLGA NP的。将进行理化的特征，以确保脂质PLGA NP将具有最佳的肝脏积累特性。 3D多细胞球体模型酒精诱导的肝纤维化将用于评估细胞相容性，最佳摄取浓度和 NP在体外渗透组织。（2）GPBAR1激动剂结合的关联和体内阐明安全性，生物分布和GPBAR1靶向NP的功能。 GPBAR1靶向，安全性和抗纤维化效应将使用广泛研究的脂质 - Plga NP进行研究，并据报道诱导的肝纤维化小鼠模型。（3）在体外和体内评估GPBAR1靶向的协同作用脂质 - Plga NP与抗纤维化疗法结合使用。在此目标中，GPBAR1的协同作用将确定纤维化衰减的激活和白介素-17a信号传导抑制后将确定脂质-PLGA NP中抗纤维化疗法的封装。 NP效率将使用组织学评估生物标志物分析和胶原蛋白测定。作为评估翻译潜力的第一步公式，我们将使用新型ALD肝纤维化在片上研究NP的治疗作用使用原代鼠细胞开发。这个创新的项目将导致开发范式转变并测试针对慢性肝病的新治疗策略，以防止其发展为HCC。