Development of phospholipid-based nanotherapeutics for treating abdominal aortic aneurysm

开发基于磷脂的纳米疗法治疗腹主动脉瘤

• 批准号: 10749980
• 负责人: Yanhong Guo
• 金额: $ 76.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749980
• 关键词: Abdominal Aortic Aneurysm; Acceleration; Adult; Aneurysm; Angiotensin II; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Aorta; Aortic Rupture; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Cardiovascular Diseases; Cause of Death; Cells; Characteristics; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical Trials; Data; Development; Dilatation - action; Disease; Dissection; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Elastases; Encapsulated; Extracellular Matrix Degradation; Fatty Acids; Formulation; Functional disorder; Genetic study; Growth; Human; Human Genetics; Image; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Lesion; Libraries; Lung diseases; Macrophage; Mediating; Medical; Michigan; Modeling; Morbidity - disease rate; Mus; Muscle function; Muscular Atrophy; Names; Nitrogen Dioxide; Nuclear; Oleic Acids; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phospholipids; Play; Property; Proteolysis; Reporting; Risk Reduction; Role; Rupture; Ruptured Aneurysm; Site; Smooth Muscle Myocytes; Stimulus; TLR4 gene; Therapeutic; Therapeutic Agents; Toxic effect; Vascular Smooth Muscle; Work; abdominal aorta; beta Aminopropionitrile; drug release kinetics; effective therapy; in vivo; lipid metabolism; mortality; mouse model; nanoparticle; nanotherapeutic; new therapeutic target; nitroalkene; novel; novel strategies; novel therapeutics; p65; particle; pharmacologic; preservation; prevent; protective effect; protective pathway; repaired; side effect; single-cell RNA sequencing; therapeutically effective; vascular inflammation

PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysm (AAA) is defined as a permanent, localized dilatation of the abdominal aorta with the potentially fatal consequence of aortic rupture. The only effective treatment for AAA is open or endovascular surgical repair when AAA patients with symptomatic or large AAA. The vast majority of AAA are below the threshold for surgical repair and 50-70% of small AAAs eventually progress to a stage requiring surgical repair. Currently, there is no effective medical therapy for these patients to reduce aneurysm growth and reduce the risk of rupture, highlighting an urgent need to develop effective medical treatments to prevent aneurysm growth and reduce the risk of rupture. Chronic inflammation and vascular smooth muscle (VSMC) dysfunction have been well documented in AAA pathogenesis in both AAA patients and animal models. Our study and others have shown that macrophage infiltration and VSMC dysfunction can be noted at a very early stage of AAA induction. Inhibition of inflammatory activation effectively reduces development and progression of AAA in animal models. However, several clinical trials have reported no efficacy of several drugs with anti- inflammatory properties to limit AAA progression, indicating a need of new strategies by targeting AAA lesions and suppressing inflammatory responses and preserving VSMC function to prevent and treat AAA. We have been developing nanoparticles (NP) to treat cardiovascular disease since 2014, in which small size NP and/or encapsulated with active therapeutic agents can be precisely applied to the target sites, such as atherosclerotic plaques and AAA lesions. Recently, we generated a novel phospholipid NP (PLN), miNano (Michigan Nanoparticle), which could accumulate in AAA lesions. Our previous studies have demonstrated that Krüppel-like factor 14 (KLF14) has strong anti-inflammatory effects by directly suppressing the nuclear factor- κB p65 expression. Recently, we found that KLF14 play an important role in maintaining VSMC function. Our preliminary studies found that nitro-oleic acid (OA-NO2), a compound currently in Phase 2 clinical trials, could induce KLF14 expression and shows VSMC protective effects in a KLF14-dependent manner. Administration of OA-NO2 protects against AAA formation and progression in mouse model. Based on these findings, we propose the central hypothesis that PLN-mediated delivery OA-NO2, a KLF14 inducer, protects against AAA pathogenesis by maintaining VSMC function and inhibiting vascular inflammation. Aim 1. Define that OA-NO2- KLF14 is a protective pathway in AAA pathogenesis. Aim 2. Develop PLN as an efficient AAA drug delivery system. Aim 3. Determine the ability of PLN-OA-NO2 to reduce AAA dissection and rupture in vivo. This study will promote the development of novel pharmacological therapies for AAA by PLN-mediated targeted drug delivery for highly efficient, more feasible and less side effects.

项目概要/摘要 腹主动脉瘤（AAA）被定义为腹主动脉永久性、局部扩张，伴有 主动脉破裂的潜在致命后果。 AAA 唯一有效的治疗方法是开放或 当AAA患者有症状或较大的AAA时进行血管内手术修复。绝大多数 AAA 是 低于手术修复的阈值，50-70% 的小 AAA 最终进展到需要手术修复的阶段 手术修复。目前，这些患者没有有效的药物治疗来减少动脉瘤的生长 并降低破裂的风险，突出表明迫切需要开发有效的医疗方法来预防 动脉瘤生长并降低破裂的风险。慢性炎症和血管平滑肌（VSMC） AAA 患者和动物模型中的 AAA 发病机制均已充分记录了功能障碍。我们的 研究和其他研究表明，巨噬细胞浸润和 VSMC 功能障碍可以在很早的时候就被发现 AAA诱导阶段。抑制炎症激活可有效减少炎症的发生和进展 动物模型中的 AAA。然而，一些临床试验报告了几种抗肿瘤药物没有疗效。 炎症特性限制 AAA 进展，表明需要针对 AAA 病变的新策略 抑制炎症反应、保护VSMC功能来预防和治疗AAA。我们有 自 2014 年以来一直在开发纳米颗粒（NP）来治疗心血管疾病，其中小尺寸 NP 和/或 封装有活性治疗剂可以精确地应用于目标部位，例如 动脉粥样硬化斑块和 AAA 病变。最近，我们生成了一种新型磷脂纳米粒子（PLN），miNano （密歇根纳米颗粒），它可以在 AAA 病变处积聚。我们之前的研究表明 Krüppel 样因子 14 (KLF14) 通过直接抑制核因子 - 具有强大的抗炎作用 κB p65 表达。最近，我们发现KLF14在维持VSMC功能中发挥着重要作用。我们的 初步研究发现，硝基油酸（OA-NO2）是一种目前处于二期临床试验的化合物，可以 诱导 KLF14 表达并以 KLF14 依赖性方式显示 VSMC 保护作用。行政 OA-NO2 可防止小鼠模型中 AAA 的形成和进展。基于这些发现，我们 提出中心假设：PLN 介导的递送 OA-NO2（一种 KLF14 诱导剂）可预防 AAA 通过维持VSMC功能和抑制血管炎症来发挥发病机制。目标 1. 定义 OA-NO2- KLF14 是 AAA 发病机制中的保护性途径。目标 2. 将 PLN 开发为有效的 AAA 药物输送 系统。目标 3. 确定 PLN-OA-NO2 减少体内 AAA 剥离和破裂的能力。这项研究 将促进PLN介导的靶向药物治疗AAA的新型药物疗法的发展 给药效率更高、更可行、副作用更少。