Development of phospholipid-based nanotherapeutics for treating abdominal aortic aneurysm

项目摘要/摘要 腹主动脉瘤(Aaa)被定义为腹主动脉的永久性、局限性扩张。 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 当AAA患者有症状或较大AAA时，行血管内手术修复。AAA的绝大多数是 低于手术修复的门槛，50%-70%的小型AAA最终进展到需要 外科修复。目前，对于这些患者，还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，突出了迫切需要开发有效的医疗方法来预防 动脉瘤的生长和降低破裂的风险。慢性炎症与血管平滑肌 在AAA患者和动物模型中，功能障碍在AAA的发病机制中都得到了很好的证明。我们的 研究和其他研究表明，巨噬细胞的渗透和VSMC功能障碍可以在很早的时候就注意到。 AAA诱导阶段。抑制炎性激活可有效延缓发展和进展 AAA在动物模型中的表达。然而，几项临床试验报告了几种具有抗肿瘤作用的药物没有疗效。 炎症特性限制了AAA的进展，表明需要通过靶向AAA病变的新策略 抑制炎症反应，保护VSMC功能，防治AAA。我们有 自2014年以来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 用活性治疗剂包裹，可以精确地应用于靶点，如 动脉粥样硬化斑块和AAA病变。最近，我们合成了一种新的磷脂NP(PLN)，Minano (密歇根纳米颗粒)，它可能在AAA病变中积聚。我们之前的研究已经证明 KRüppel-like factor14(KLF14)通过直接抑制核因子而具有强大的抗炎作用。 κB p65的表达。最近，我们发现KLF14在维持VSMC功能中起着重要作用。我们的 初步研究发现，目前处于第二阶段临床试验的化合物硝基油酸(OA-NO2)可以 诱导KLF14表达，并以KLF14依赖的方式显示VSMC的保护作用。行政管理 OA-NO2对小鼠AAA形成和进展的保护作用。基于这些发现，我们 提出PLN介导的递送OA-NO2(KLF14诱导剂)预防AAA的中心假设 发病机制主要通过维持VSMC功能和抑制血管炎症来实现。目标1.定义OA-NO2- KLF14是AAA发病机制中的保护性通路。目的2.发展PLN作为一种有效的AAA药物输送 系统。目的3.测定PLN-OA-NO2在体内减少腹主动脉夹层和破裂的能力。本研究 将通过PLN介导的靶向药物促进AAA药物治疗的发展 给药效率高，更可行，副作用少。

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.