Date of Award

2017

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Engineering

Department

Washkewicz College of Engineering

First Advisor

Ramamurthi, Anand

Subject Headings

Biomedical Engineering

Abstract

Abdominal aortic aneurysms (AAAs) are characterized by the loss of elasticity in the aorta wall leading to a chronic increase in diameter and resulting in rupture. This is due to the lack of regeneration of elastic fibers and chronic proteolytic breakdown of elastic fibers within the aorta mediated by matrix metalloproteinases (MMPs), specifically MMP-2 and -9. Previous studies in our lab have shown cationic amphiphile-surface functionalized poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with doxycycline (DOX) to inhibit MMP activity and stimulate elastic matrix synthesis, effects we attributed to both low doses (< 10 mg/ml) of DOX released and independent effects of cationic amphiphile pendant groups on the NP surface. This promises application of these NPs to arrest or regress AAA growth since high oral DOX dosing inhibits new elastic matrix formation in the AAA wall and has undesirable side effects. In this study, we investigated feasibility of antibody-based active targeting of intravenously infused NPs to the AAA wall. Cathepsin K, a cysteine protease, is a biomarker for AAA and overexpressed in abdominal aortic aneurysm tissue making it an ideal target moiety. We have shown using a covalent conjugation method of modifying the surface of the NPs with a cathepsin K antibody resulted in a more robust antibody attachment which did not affect the DOX release profile. Cathepsin K expression was confirmed to be localized on the cell surface and utilizing cathepsin K Ab-conjugated NPs, we demonstrated an increased NP localization to the cathepsin K overexpressing cells in vitro and ex vivo. Importantly, the DOX-loaded NPs demonstrated pro-elastogenic and anti-proteolytic effects in aneurysmal smooth muscle cells supporting their use as regenerative therapies to arrest and regress AAA growth. Preliminary data has been collected indicating cathepsin K Ab-conjugated NP targeting to AAAs in elastase-injured rat models. The study outcomes support the feasibility of using cathepsin K Ab-conjugated NPs as a targeted therapy for elastic matrix regeneration in AAA tissue and will serve as a basis for already initiated follow up studies to assess NP biodistribution, in situ retention in the AAA wall, and safety as a function of time.

Download
COinS