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

纳米颗粒介导的肝巨噬细胞靶向减轻酒精性肝病炎症

• 批准号: 10352578
• 负责人: Jyothi Unnikrishna Menon
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-20 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352578
• 关键词: Adult; Adverse effects; Agonist; Alcohol abuse; Alcoholic Liver Diseases; Alcohols; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Bile Acids; Biodistribution; Biological Assay; Biological Markers; C57BL/6 Mouse; Caliber; Cancer Etiology; Cell Culture Techniques; Cells; Cessation of life; Chitosan; Cholestasis; Chronic; Cirrhosis; Clinic; Clinical; Collaborations; Collagen; Combined Modality Therapy; Coupled; Data; Development; Dexamethasone; Diagnosis; Disease; Disease model; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Encapsulated; Enzyme-Linked Immunosorbent Assay; Ethanol; Exhibits; Fasting; Fibrosis; Formulation; GPBAR1 gene; GTP-Binding Proteins; Glycolates; Goals; Hepatic; Histology; Human; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intravenous; Investigation; Kupffer Cells; Lead; Ligands; Liver; Liver diseases; Malignant Neoplasms; Mediating; Modeling; Molecular Target; Outcome; Pharmaceutical Preparations; Polymers; Positioning Attribute; Primary carcinoma of the liver cells; Production; Property; Regenerative capacity; Reproducibility; Research; Research Project Grants; Safety; Site; Specificity; Stimulus; Study models; Surface; Testing; Therapeutic; Time; Toxic effect; Translational Research; Treatment Efficacy; United States; Validation; Work; alcohol exposure; base; biodegradable polymer; biomaterial compatibility; chronic liver disease; chronic liver inflammation; collaborative approach; cytokine; design; design verification; drug release kinetics; effective therapy; efficacy validation; in vivo; in vivo evaluation; innovation; liver inflammation; liver injury; macrophage; mortality; mouse model; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical assessment; receptor; response; targeted treatment; treatment strategy

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.

抽象的 由于酗酒持续性肝损伤引起的慢性和未解决的肝感染会导致纤维化， 肝硬化，有时甚至是肝细胞癌（HCC） - 这是与癌症相关的禁食原因 世界上的死亡率。美国近450万成年人患有慢性肝病。有效的 由于较差 药代动力学，毒性和缺乏当前疗法的特异性。纳米颗粒（NP）介导的靶向药物 递送可以达到高肝浓度和低全身浓度的药物。我们有 证明NP可以针对G蛋白偶联的胆汁酸受体1（GPBAR1） kupffer细胞，以调节肝炎炎症反应。用pH响应聚合物涂层NP 通过支持将封装药物释放到该动力学中的药物释放动力学的进一步控制 酸性炎症微环境。因此，这个R21项目的总体目标是开发一个kupffer 靶向细胞的双功能NP公式，可用于靶向刺激GPBAR1和 抗炎疗法的同时pH响应性释放。我们假设联合动作 GPBAR1刺激和抗炎疗法将对缓解慢性肝脏产生额外的影响 与酒精性肝病有关的炎症。我们提出的目标是：目标1：评估体内 针对GPBAR1靶向的NP的靶向能力和生物分布。我们将研究和优化目标 我们可生物降解的聚合物NPs表面的功能和生物分布，装饰有INT-777-有效的 GPBAR1激动剂，使用广泛使用的酒精性肝病的慢性增长动物模型。目标2：到 研究设计的NPS在体外和体内的治疗效率。基于优化属性 在AIM 1中，NP将进一步修改以纳入抗炎药物地塞米松，并进行了测试 针对经过酒精处理的肝芯片模型和慢性饮食模型，以确定其 药代动力学和药效学（PK/PD）特性。我们将使用组织学，生物标志物分析，胶原蛋白 测定和细胞因子ELISA研究我们的双功能NP是否可以显着减轻慢性肝 与没有INT-777的免费药物或NP相比，炎症。我们的结果将导致范式转变 慢性肝脏注射新的治疗策略的开发和测试，紧急情况 需要开发以及安全，一致的有效疗法。