Theranostic approach to treat abdominal aortic aneurysms

项目摘要 腹主动脉瘤（AAA）是一种以动脉破坏为特征的退行性疾病， 结构和随后的扩张，最终可能导致致命的破裂。这是第13个主要原因， 死亡在美国 筛查和选择性手术干预的早期发现是减少 死亡率 AAA如果男性的直径超过5.5厘米或5 破裂是对病人生命的最大威胁。我 对于女性，建议手术放置血管移植物。然而，几个小动脉瘤可能 而一些更大的却永远不会破裂 多达90%的检测到的AAAs是小的，缺乏指示， 手术;这些病人处于"观察等待"状态，没有任何治疗。主动脉直径随时间的变化仅 用于研究疾病进展的指标。 没有方法可以确定损坏的程度， 壁或弱化和膨胀的壁是主动脉破裂的高风险。再无 药物治疗以防止AAA进展。 我们已经开发了一种新的纳米颗粒（NP）递送系统，其仅靶向降解的血管弹性蛋白， 早期动脉瘤的标志我们还发现了弹性蛋白的稳定和再生潜力， 多酚-五没食子酰葡萄糖（PGG）。 我们假设弹性膜降解可以通过以下方法测量： 金纳米颗粒对降解的弹性膜的位点特异性靶向，并且它将与壁相关 强度和提供断裂潜力指标。我们进一步假设， 动脉瘤通过稳定残余弹性蛋白和再生失去的弹性蛋白将阻止扩张和最终的 AAA破裂 具体目标1我们将测试金纳米颗粒可以靶向降解的弹性膜的假设 在AAA三种不同动物模型中体内，microCT成像将提供定量弹性膜 基于黄金积累的损害评估。在目标2中，我们将检验基于白蛋白， 靶向纳米颗粒将PGG递送到AAA位点以稳定弹性膜并增加弹性蛋白基质 沉积，从而在三种不同的AAA动物模型中再次允许AAA消退。 在 我们的研究将是首次尝试通过纳米粒子靶向AAA递送显像剂和药物 系统.我们的成像研究将提供局部壁强度的估计。这一重要信息沿着 通过计算研究确定壁应力将有助于预测主动脉的未来破裂。如果 如果成功，我们还设想药物靶向将阻止AAA扩张并恢复患者的健康主动脉。

Project Summary Abdominal Aortic aneurysms (AAA) are degenerative diseases characterized by destruction of arterial architecture and subsequent dilation that may eventually lead to fatal ruptures. It is the 13th leading cause of death in US. Screening and early detection with elective surgical intervention is an effective way to decrease mortality in AAA f the diameter exceeds 5.5 cm for men or 5 , where rupture is the great threat to a patient's life. I cm for women, surgical placement of vascular grafts is recommended. However; several small aneurysms may rupture while some larger ones never do. As many as 90% of detected AAAs are small and lack indications for surgery; these patients are on “watchful waiting” without any treatment. Aortic diameter change with time is only measure used to study progression of the disease. No method is available to determine the extent of damage to the wall or which weakened and ballooned walls are at high-risk for aortic rupture. Neither is there any pharmacological treatment to prevent AAA progression. We have developed a novel nanoparticle (NP) delivery system that targets only degraded vasculature elastin, a hallmark of early stage aneurysms. We have also discovered elastin stabilizing and regeneration potential of polyphenol-pentagalloyl glucose (PGG). We hypothesize that elastic lamina degradation can be measured by site-specific targeting of gold nanoparticle to the degraded elastic lamina and that it will correlate with wall strength and provide index for rupture potential. We further hypothesize that increasing the strength of the aneurysmal aorta by stabilizing residual elastin and regenerating lost elastin will prevent expansion and ultimate rupture of AAA. Specific Aim 1 we will test the hypothesis that gold nanoparticles can be targeted to degraded elastic lamina in vivo in three distinct animal models of AAA, and that microCT imaging will provide quantitative elastic lamina damage assessment based on gold accumulation. In Aim 2 we will test test the hypothesis that albumin-based, targeted nanoparticles will deliver PGG to the AAA site to stabilize elastic lamina and increase elastin-matrix deposition, thus allowing AAA regression again in three distinct animal models of AAA. In Ours will be the first attempt to deliver imaging agents and drugs to AAA via nanoparticle-based targeting systems. Our imaging study will provide estimation of local wall strength. This important information along with wall stress determination from computational studies will be useful to predict future rupture of the aorta. If successful, we also envision that drug targeting will halt AAA expansion and restore healthy aorta in patients.