Targeted Delivery of Heparin and LMWH Using a Fibrin Antibody Prevents Restenosis

Atherosclerosis. 2004 Sep;176(1):73-81. doi: 10.1016/j.atherosclerosis.2004.05.006.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Anticoagulants / blood
  • Anticoagulants / pharmacology*
  • Carotid Arteries / pathology
  • Carotid Stenosis / drug therapy*
  • Carotid Stenosis / prevention & control
  • Cross-Linking Reagents / pharmacology
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Fibrin / immunology*
  • Heparin, Low-Molecular-Weight / blood
  • Heparin, Low-Molecular-Weight / pharmacology*
  • Rabbits
  • Secondary Prevention
  • Stents*
  • Thrombosis / prevention & control
  • Tunica Intima / pathology

Substances

  • Antibodies
  • Anticoagulants
  • Cross-Linking Reagents
  • Heparin, Low-Molecular-Weight
  • Fibrin