Date of Award

8-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Committee Member

Dr. Narendra Vyavahare, Committee Chair

Committee Member

Dr. Martine Laberge

Committee Member

Dr. Jeoung Soo Lee

Committee Member

Dr. Alexey Vertegel

Committee Member

Dr. Bruce Gray

Abstract

Abdominal aortic aneurysm (AAA) is focal ballooning and dilation of abdominal aorta. AAAs are the 13th primary cause of death in the US, taking the lives of approximately 15,000 Americans each year 1. The best prevention of AAA is early detection when the AAA is smaller than 3 cm. The only current treatment option for well-developed AAA is surgical repair of the aneurysmal vessel. Since the enactment of the Screening Abdominal Aortic Aneurysms Very Efficiently Act (SAAVE) act, patients with Medicare are covered for one-time ultrasound imaging for aneurysm, which allows smaller scale AAAs to be discovered. Unfortunately, after this initial detection there is no currently known treatment to slow the growth of these aneurysms. Monitoring can be continued through the use of ultrasound imaging or plain film radiography, which shows calcification related to the AAA, but there is no effective way to show a full picture of focal wall weakening 2. When the AAA has a diameter greater than 5.5 cm, elective surgery is typically performed as the risk of surgery is less than the risk of a ruptured AAA. Excessive activity of metalloproteinases (MMPs) has been associated with aortic elastin damage and degeneratio3. Also AAA is often associated with calcification, which increases the risk of AAA rupture 4. Based on this knowledge, we hypothesized that combined treatment MMP inhibitors locally to stop the degradation of elastin, and pentagalloyl glucose (PGG) to regenerate lost elastin can be an effective treatment option for early to middle stage aneurysms in order to prevent disease progression. Furthermore, we hypothesized that calcification associated with well-developed AAA can be removed first with ethylene diamime tetraacetic acid (EDTA), a well-known metal ion chelator and then degraded elastin can be regenerated with PGG. The overall goal of this study was to develop a minimally invasive, non-toxic, targeted vascular drug delivery system that both prevents elastin degradation and aids elastin regeneration, thereby acting as a multi-functional treatment option for elasto-degenerative vascular diseases including AAAs. In order to achieve this goal, we used nanoparticles (NPs) developed in our laboratory to target degraded elastin by conjugating elastin antibody that specifically recognizes only degraded elastin. First, using calcium chloride-induced AAA rat model, we show targeted delivery of such nanoparticles loaded MMP inhibitor (BB-94) lead to suppression of MMP activity in abdominal aortic aneurysms and prevented aneurysmal expansion. Next, we demonstrated that nanoparticles can be loaded with PGG. In AAA model in rats, we show PGG can be delivered at the site of AAA by targeted NPs. Such PGG delivery inhibited elastin degradation and lead to suppression of AAA. Finally, we tested whether moderate size calcified aneurysms could be reversed by dual therapy. We created moderate size AAA in rats by calcium chloride injury, and then first delivered EDTA loaded NPs systemically to remove calcification followed by delivery of PGG loaded NPs. Only dual therapy showed reversal of calcification in the aorta as well as reversal of AAA and regeneration of elastic lamina. NPs with EDTA alone or blank NPs did not cause regeneration of elastic lamina in the aorta.

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