Theranostic approach to treat abdominal aortic aneurysms

项目摘要 腹主动脉瘤(Aaa)是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。它是13个主要的原因 美国的死亡事件。 选择性手术干预的筛查和早期发现是减少的有效方法 年死亡率 男性直径超过5.5厘米或5厘米。 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，几个小的动脉瘤可能 破裂，而一些较大的则永远不会。 高达90%的检测到的AAA是小的，并且没有迹象表明 手术；这些患者在没有任何治疗的情况下处于“警惕等待”状态。主动脉直径随时间的变化只是 用于研究疾病进展的指标。 目前还没有方法来确定对 动脉壁变薄或膨胀是主动脉破裂的高危因素。也没有 防止AAA进展的药物治疗。 我们已经开发了一种新的纳米颗粒(NP)递送系统，它只针对降解的血管弹性蛋白， 早期动脉瘤的特征。我们还发现了弹性蛋白稳定和再生的潜力 多酚-五合金基葡萄糖(PGG)。 我们假设弹性薄板退化可以通过以下方式测量 金纳米颗粒在降解弹性膜上的定位靶向及其与壁面的关联 强度，并提供破裂可能性的指标。我们进一步假设，增加经济增长的力量 动脉瘤通过稳定残留的弹性蛋白和再生丢失的弹性蛋白来防止扩张和最终 腹主动脉破裂。 具体目标1我们将测试金纳米颗粒可以靶向降解的弹性层的假设 在三种不同AAA动物模型中，MicroCT成像将提供定量的弹性板层 基于黄金积累的损失评估。在目标2中，我们将测试基于白蛋白的假设， 靶向纳米颗粒将PGG输送到AAA部位，以稳定弹性膜并增加弹性蛋白基质 因此，在三种不同的AAA动物模型中，AAA可以再次回归。 在……里面 我们将首次尝试通过基于纳米颗粒的靶向向AAA输送显像剂和药物 系统。我们的成像研究将提供局部壁强度的估计。这一重要信息以及 通过计算研究确定的壁应力将有助于预测未来的主动脉破裂。如果 如果成功，我们还设想药物靶向将阻止AAA的扩张，并恢复患者健康的主动脉。

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.