Targeted delivery of heparin and LMWH using a fibrin antibody prevents restenosis.
This study investigates a stent-less local delivery system for anti-restenotic agents utilizing antibodies to cross-linked fibrin (XLF). Heparin and low molecular weight heparin (LMWH) were conjugated to an antibody to cross-linked fibrin D-dimer (1D2). Rabbit right carotid arteries were injured with a balloon catheter, then the animals were given a bolus injection of 40 microg/kg 1D2-heparin (26-70 microg/kg heparin) or 1D2-LMWH (29-80 microg/kg LMWH) conjugates or controls of saline (0.5 ml/kg), heparin (150 U/kg), LMWH (2 mg), or 1D2 (40 microg/kg), with or without a heparin bolus and sacrificed after 2 weeks (8 groups, n = 6/group). The injured artery of rabbits given 1D2-heparin or 1D2-LMWH conjugates had reduced neointimal development, with decreased luminal narrowing and positive remodelling compared with animals given control drugs. Animals given 1D2-heparin conjugate (with a heparin bolus) had three to five times more endothelial cells than the rabbits given saline or unconjugated heparin, while rabbits given 1D2-LMWH conjugate had up to 59% fewer neointimal cells than those given unconjugated drugs. There was little difference in extracellular matrix organization or composition. Thus cross-linked fibrin-antibodies can site-deliver anti-restenotic agents to injured areas of the artery wall where they influence wall remodelling and endothelial and neointimal cell number, reducing neointimal formation without systemic complications. Local delivery of anti-restenotic agents should minimise systemic effects, bleeding complications and potentially the cost of treatment due to a single, lower dose.
Centre for Research in Vascular Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia. a.thomas@Bristol.ac.uk
Anita C
AC
Thomas
Julie H
JH
Campbell
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000925:Anticoagulants / Q000097:blood / Q000494:pharmacology*; D002339:Carotid Arteries / Q000473:pathology; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000517:prevention & control; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005337:Fibrin / Q000276:immunology*; D006495:Heparin, Low-Molecular-Weight / Q000097:blood / Q000494:pharmacology*; D011817:Rabbits; D055502:Secondary Prevention; D015607:Stents; D013927:Thrombosis / Q000517:prevention & control; D017539:Tunica Intima / Q000473:pathology
D000906:Antibodies; D000925:Anticoagulants; D003432:Cross-Linking Reagents; D006495:Heparin, Low-Molecular-Weight; D005337:Fibrin