Conjugation of an antibody to cross-linked fibrin for targeted delivery of anti-restenotic drugs.
There is an urgent need to treat restenosis, a major complication of the treatment of arteries blocked by atherosclerotic plaque, using local delivery techniques. We observed that cross-linked fibrin (XLF) is deposited at the site of surgical injury of arteries. An antibody to XLF, conjugated to anti-restenotic agents, should deliver the drugs directly and only to the site of injury. An anti-XLF antibody (H93.7C.1D2/48; 1D2) was conjugated to heparin (using N-succinimidyl 3-(2-pyridyldithio)propionate), low molecular weight heparin (LMWH) (adipic acid dihydrazide) and rapamycin (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide), and the conjugates purified and tested for activity before use in vivo. Rabbits had their right carotid arteries de-endothelialised and then given a bolus of 1D2-heparin, 1D2-LMWH or 1D2-rapamycin conjugate or controls of saline, heparin, LMWH, rapamycin or 1D2 (+/-heparin bolus) and sacrificed after 2 or 4 weeks (12 groups, n=6/group). Rabbits given any of the conjugates had minimal neointimal development in injured arteries, with up to 59% fewer neointimal cells than those given control drugs. Rabbits given 1D2-heparin or 1D2-LMWH had an increased or insignificant reduction in luminal area, with positive remodelling, while the medial and total arterial areas of rabbits given 1D2-rapamycin were not affected by injury. Arteries exposed to 1D2-heparin or 1D2-rapamycin had more endothelial cells than rabbits given control drugs. Thus, XLF-antibodies can site-deliver anti-restenotic agents to injured areas of the artery wall, where the conjugates can influence remodelling, re-endothelialisation and neointimal cell density, with reduced neointimal formation.
Thomas
Anita C
AC
Centre for Research in Vascular Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia. a.thomas@Bristol.ac.uk
Campbell
Julie H
JH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000906:Antibodies / Q000737:chemistry* / Q000627:therapeutic use*; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D003432:Cross-Linking Reagents; D016503:Drug Delivery Systems; D004591:Electrophoresis, Polyacrylamide Gel; D005337:Fibrin / Q000737:chemistry / Q000276:immunology*; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D006493:Heparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use; D013388:Succinimides / Q000737:chemistry
D000900:Anti-Bacterial Agents; D000906:Antibodies; D003432:Cross-Linking Reagents; D006495:Heparin, Low-Molecular-Weight; D013388:Succinimides; C018151:N-succinimidyl 3-(2-pyridyldithio)propionate; D005337:Fibrin; D006493:Heparin; D020123:Sirolimus