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Title page for ETD etd-03122015-130201


Type of Document Dissertation
Author Hofmeister, Lucas Hudson
Author's Email Address lucas.h.hofmeister@vanderbilt.edu
URN etd-03122015-130201
Title Development of hemodynamic targeted theranostic nanoparticles for the prevention of atherosclerosis
Degree PhD
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Hak-Joon Sung Committee Chair
David Harrison Committee Co-Chair
Craig Duvall Committee Member
Kasey Vickers Committee Member
Todd Giorgio Committee Member
Keywords
  • Phage Display
  • Liposome
  • Nanoparticle
  • Atherosclerosis
  • Tetrahydrobiopterin
  • Disturbed flow
Date of Defense 2015-03-10
Availability unrestricted
Abstract
In regions of the circulation where vessels are straight and unbranched, blood flow is laminar and unidirectional. In contrast, at sites of curvature, branch points and regions distal to stenoses blood flow becomes disturbed. Atherosclerosis preferentially develops in these regions of disturbed blood flow. Current therapies for atherosclerosis are systemic, and may not sufficiently target these atheroprone regions. In this study, we sought to leverage the alterations on the luminal surface of endothelial cells caused by this atheroprone flow for nanocarrier targeting. In vivo phage display was used to discover unique peptides that selectively bind to atheroprone regions in the mouse partial carotid artery ligation model. The peptide GSPREYTSYMPH (PREY) was found to bind 4.5-fold more avidly to the region of disturbed flow, and was used to form targeted liposomes. When administered intravenously, PREY-targeted liposomes preferentially accumulated in endothelial cells in the partially occluded carotid artery and other areas of disturbed flow. Proteomic analysis and immunoblotting indicated that fibronectin and Filamin A were preferentially bound by PREY-nanocarriers in vessels with disturbed flow. In additional experiments, PREY-nanocarriers were used therapeutically to deliver the nitric oxide synthase co-factor tetrahydrobiopterin (BH4), which we have previously shown to be deficient in regions of disturbed flow. This intervention increased vascular BH4 and reduced vascular superoxide in the partially ligated artery in wild-type mice, and reduced plaque burden in the partially ligated left carotid artery of fat fed atheroprone mice (ApoE-/-). Targeting atheroprone sites of the circulation with functionalized nanocarriers provides a new approach for prevention of early atherosclerotic lesion formation.
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