Theranostic approach to treat abdominal aortic aneurysms

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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.