Edward S M Bahnson1,2, Hussein A Kassam1,2, Tyson J Moyer1,3, Wulin Jiang1,2, Courtney E Morgan1,2, Janet M Vercammen1,2, Qun Jiang1,2, Megan E Flynn1,2, Samuel I Stupp1,3,4,5,6, Melina R Kibbe1,2. 1. 1 Simpson Querrey Institute for BioNanotechnology, Northwestern University , Chicago, Illinois. 2. 2 Department of Surgery, Feinberg School of Medicine, Northwestern University , Chicago, Illinois. 3. 3 Department of Materials Science and Engineering, Northwestern University , Evanston, Illinois. 4. 4 Department of Chemistry, Northwestern University , Evanston, Illinois. 5. 5 Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, Illinois. 6. 6 Department of Biomedical Engineering, Northwestern University , Evanston, Illinois.
Abstract
AIMS: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. 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. RESULTS: 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. INNOVATION: 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. CONCLUSION: We successfully 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.
AIMS: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. 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. RESULTS: 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. INNOVATION: 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. CONCLUSION: We successfully 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.
Authors: J M Lablanche; G Grollier; J R Lusson; J P Bassand; G Drobinski; B Bertrand; S Battaglia; B Desveaux; Y Juillière; J M Juliard; J P Metzger; P Coste; J C Quiret; J L Dubois-Randé; P D Crochet; B Letac; J Boschat; P Virot; G Finet; H Le Breton; B Livarek; F Leclercq; T Béard; T Giraud; M E Bertrand Journal: Circulation Date: 1997-01-07 Impact factor: 29.690
Authors: H E von der Leyen; G H Gibbons; R Morishita; N P Lewis; L Zhang; M Nakajima; Y Kaneda; J P Cooke; V J Dzau Journal: Proc Natl Acad Sci U S A Date: 1995-02-14 Impact factor: 11.205
Authors: M Ziche; L Morbidelli; E Masini; S Amerini; H J Granger; C A Maggi; P Geppetti; F Ledda Journal: J Clin Invest Date: 1994-11 Impact factor: 14.808
Authors: Nicholas E Buglak; Jennifer Lucitti; Pablo Ariel; Sophie Maiocchi; Francis J Miller; Edward S M Bahnson Journal: Cardiovasc Res Date: 2021-01-21 Impact factor: 10.787