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.

项目总结/摘要 腹主动脉瘤（AAA）定义为腹主动脉的永久性局部扩张， 主动脉破裂的潜在致命后果AAA的唯一有效治疗方法是开放或 腹主动脉瘤患者出现症状或较大腹主动脉瘤时行腔内手术修复。绝大多数AAA 低于手术修复的阈值，50-70%的小AAA最终进展到需要 外科修复目前，对于这些患者没有有效的药物治疗来减少动脉瘤生长 并降低破裂的风险，这突出表明迫切需要开发有效的医学治疗方法， 动脉瘤生长，降低破裂风险。慢性炎症与血管平滑肌（VSMC） 功能障碍在AAA患者和动物模型中的AAA发病机制中已有很好的记录。我们 研究和其他研究已经表明，巨噬细胞浸润和VSMC功能障碍可以在非常早期 AAA诱导阶段。抑制炎症激活有效地减少了发展和进展 AAA在动物模型中然而，几项临床试验报告了几种药物与抗- 限制AAA进展的炎症特性，表明需要通过靶向AAA病变的新策略 抑制炎性反应，保护VSMC功能，预防和治疗AAA。我们有 自2014年以来，该公司一直在开发用于治疗心血管疾病的纳米颗粒（NP），其中小尺寸NP和/或 包封有活性治疗剂的药物可以精确地应用于靶部位，例如 动脉粥样硬化斑块和AAA病变。最近，我们产生了一种新的磷脂NP（PLN），miNano （Michigan Nanoparticle），可在AAA病变中蓄积。我们之前的研究表明， Krüppel样因子14（KLF 14）通过直接抑制核因子- κB p65表达。近年来，我们发现KLF 14在维持VSMC功能中起重要作用。我们 初步研究发现，硝基油酸（OA-NO2），一种目前处于2期临床试验的化合物， 诱导KLF 14表达，并以KLF 14依赖性方式显示VSMC保护作用。管理 OA-NO2在小鼠模型中对AAA形成和进展具有保护作用。基于这些发现，我们 我提出了一个中心假设，即PLN介导的OA-NO2（一种KLF 14诱导剂）递送可预防AAA 通过维持VSMC的功能和抑制血管炎症而发病。目标1.定义OA-NO2- KLF 14是AAA发病机制中的保护性通路。目标2.将PLN开发为高效的AAA药物输送 系统目标3.确定PLN-OA-NO2在体内减少AAA夹层和破裂的能力。本研究 将促进PLN介导的靶向药物治疗AAA的新药物的开发 高效、可行、副作用小的给药途径。