title: Phage-display-guided nanocarrier targeting to atheroprone vasculature.
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 cofactor 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 promising approach for prevention of early atherosclerotic lesion formation.
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Lucas H
authors.initials: LH
authors.lastname: Hofmeister
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Sue Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Norlander
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Kim Ramil C
authors.initials: KR
authors.lastname: Montaniel
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: †Department of Biomedical Engineering, ‡Division of Clinical Pharmacology, §Center for Vascular Biology, and ∥Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Hak-Joon
authors.initials: HJ
authors.lastname: Sung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism*; D004198:Disease Susceptibility; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050997:Nanomedicine / Q000379:methods*; D049329:Nanostructures; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D019151:Peptide Library
chemical_list: D001057:Apolipoproteins E; D004337:Drug Carriers; D009842:Oligopeptides; D019151:Peptide Library; D001708:Biopterins; C003402:sapropterin
keywords: disturbed flow atherosclerosis; liposome; phage display; tetrahydrobiopterin