title: The formation of an anti-restenotic/anti-thrombotic surface by immobilization of nitric oxide synthase on a metallic carrier.
abstract: Coronary stenosis due to atherosclerosis, the primary cause of coronary artery disease, is generally treated by balloon dilatation and stent implantation, which can result in damage to the endothelial lining of blood vessels. This leads to the restenosis of the lumen as a consequence of migration and proliferation of smooth muscle cells (SMCs). Nitric oxide (NO), which is produced and secreted by vascular endothelial cells (ECs), is a central anti-inflammatory and anti-atherogenic player in the vasculature. The goal of the present study was to develop an enzymatically active surface capable of converting the prodrug l-arginine, to the active drug, NO, thus providing a targeted drug delivery interface. NO synthase (NOS) was chemically immobilized on the surface of a stainless steel carrier with preservation of its activity. The ability of this functionalized NO-producing surface to prevent or delay processes involved in restenosis and thrombus formation was tested. This surface was found to significantly promote EC adhesion and proliferation while inhibiting that of SMCs. Furthermore, platelet adherence to this surface was markedly inhibited. Beyond the application considered here, this approach can be implemented for the local conversion of any systemically administered prodrug to the active drug, using catalysts attached to the surface of the implant.
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Alagem-Shafir
authors.affiliation: Department of Biotechnology Engineering, ORT Braude College of Engineering, Karmiel 21982, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Kivovich
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Tzchori
authors.affiliation: Ruth and Bruce Rappaport faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Lanir
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Falah
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel; Ruth and Bruce Rappaport faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: M Y
authors.initials: MY
authors.lastname: Flugelman
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: U
authors.initials: U
authors.lastname: Dinnar
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel; Ruth and Bruce Rappaport faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Rambam Health Care Campus, Haifa, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Beyar
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Lotan
authors.affiliation: Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Biotechnology Engineering, ORT Braude College of Engineering, Karmiel 21982, Israel. Electronic address: sivan.sarit@gmail.com.
authors.forename: S S
authors.initials: SS
authors.lastname: Sivan
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D023903:Coronary Restenosis / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D004800:Enzymes, Immobilized / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010973:Platelet Adhesiveness / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013193:Stainless Steel / Q000494:pharmacology*; D015607:Stents; D013499:Surface Properties; D013927:Thrombosis / Q000473:pathology*
chemical_list: D004800:Enzymes, Immobilized; D013193:Stainless Steel; D012710:Serum Albumin, Bovine; D019001:Nitric Oxide Synthase
keywords: Drug targeting; Hemocompatibility; Immobilized enzyme; Nitric oxide; Restenosis