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Title: Targeted nitric oxide delivery by supramolecular nanofibers for the prevention of restenosis after arterial injury

Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. Here we sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. As a result, structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. In conclusion, we successfullymore » synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases« less
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1]
  1. Northwestern Univ., Chicago, IL (United States)
  2. Northwestern Univ., Chicago, IL (United States); Northwestern Univ., Evanston, IL (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Antioxidants and Redox Signaling
Additional Journal Information:
Journal Volume: 24; Journal Issue: 8; Journal ID: ISSN 1523-0864
Publisher:
Mary Ann Liebert, Inc.
Research Org:
Northwestern Univ., Chicago, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1342729