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

• 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
• 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

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.

摘要 肝细胞癌(肝细胞癌)，是全球癌症相关死亡人数上升最快的原因， 20%的存活率，每年影响美国超过4.1万人。重酒 消费导致脂肪肝、肝炎和肝硬变已被确定为肝癌的关键危险因素 发展。目前针对酒精性肝病(ALD)和相关纤维化的治疗方法是非特异性的 效果不佳。戒酒仍然是ALD治疗的黄金标准，以防止进展为肝细胞癌， 然而，这往往受到合规性差的阻碍。这项提议的目标是发展一部小说 多功能纳米微粒平台治疗酒精性肝纤维化的实验研究 G蛋白偶联胆汁酸受体(Gpbar1)的靶向激活与抗纤维化药物传递NPS将会 也释放胶原酶，以促进NP更大程度地渗透到纤维化的肝组织中。我们假设(I) NP介导Kupffer细胞膜蛋白Gpbar1的靶向激活 肝细胞，将抑制与肝癌发生有关的核因子-kβ和STAT3信号，以及(Ii)靶向 Gpbar1的激活和抗纤维化药物的同时释放将协同抑制纤维化生物标记物 表达和细胞因子信号转导，导致纤维化的减弱。我们的初步调查 合作研究小组证实，在活体小鼠的KCs中，NPs可以选择性地积聚 模特们。我们提出的目标是：(1)肝组织渗透特性的表征和体外评价 含胶原酶的脂质-PLGA纳米粒。将进行物理化学表征，以确保 脂质-PLGA纳米粒将具有在肝脏中蓄积的最佳特性。一种三维多细胞球体模型 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 纳米粒在体外对组织的渗透作用。(2)Gpbar1激动剂的掺入和体内安全性的阐明； NPs的生物分布和Gpbar1靶向能力。Gpbar1的靶向性、安全性和抗纤维化作用 脂质-PLGA纳米粒将使用被广泛研究和报道的四氯化碳加酒精进行研究 诱导小鼠肝纤维化模型。(3)Gpbar1靶向的体内外协同效应评价 脂质-PLGA纳米粒与抗纤维化治疗相结合。在这个目标中，Gpbar1的协同效应 激活和抑制白介素17A信号对纤维化的抑制作用将在下文中确定 在脂质-PLGA纳米粒中包裹抗纤维化治疗。NP的疗效将通过组织学进行评估， 生物标记物分析和胶原蛋白分析。作为评估翻译潜力的第一步， 配方后，我们将使用新型ALD芯片上的肝纤维化来研究NPs的治疗效果 利用原代小鼠细胞研制而成。这一创新项目将导致发展范式的转变 以及测试针对慢性肝病的新治疗策略，以防止它们发展为肝细胞癌。