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

摘要 慢性和未解决的肝脏炎症由于持续性肝损伤酒精滥用可导致纤维化， 肝硬化和最终肝细胞癌（HCC）-这是癌症相关的快速增长的原因， 死亡率在世界上。在美国，近450万成年人患有慢性肝病。有效 针对肝脏炎症的安全治疗策略仍然是未满足的临床需求， 药物代谢动力学、毒性和目前治疗缺乏特异性。纳米粒介导的靶向药物 递送可以实现药物的高肝脏浓度和低全身浓度。我们有 证明了NP可以靶向G蛋白偶联胆汁酸受体1（Gpbar 1）， 枯否细胞，调节肝脏炎症反应。用pH响应性聚合物涂覆NP 通过促进包封的药物释放到 酸性炎症微环境。因此，该R21项目的首要目标是开发一个Kupffer 细胞靶向双功能NP制剂，其可用于靶向刺激Gpbar 1， 抗炎治疗剂的pH响应性同时释放。我们假设， Gpbar 1刺激和抗炎治疗将在缓解慢性肝病方面具有叠加效应。 与酒精性肝病相关的炎症。我们提出的目的是：目的1：评价体内 靶向Gpbar 1的NP的靶向能力和生物分布。我们将研究和优化目标 我们的可生物降解聚合物纳米颗粒表面装饰INT-777-一种有效的 gpbar 1激动剂，使用广泛使用的酒精性肝病慢性加狂欢动物模型。目标2： 研究所设计的纳米粒在体外和体内的治疗效果。基于优化的性能 在目标1中，纳米颗粒将被进一步修饰以掺入抗炎药物地塞米松，并测试 对照酒精处理的肝片模型和慢性加狂欢动物模型，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 实验和细胞因子ELISA来研究我们的双功能NPs是否可以显著减轻慢性肝硬化。 与游离药物或不含INT-777的NP相比，炎症。我们的结果将导致 开发和测试慢性肝脏炎症的新治疗策略，其中迫切需要 需要开发安全和持续有效的治疗方法。

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.