Influence of local delivery of the protein tyrosine kinase receptor inhibitor tyrphostin-47 on smooth-muscle cell proliferation in a rat carotid balloon-injury model

• Published in: The American heart journal Vol. 133; no. 3; pp. 329 - 334
• Main Authors: Gottsauner-Wolf, Michael, Jang, Yangsoo, Lincoff, A.Michael, Cohen, Joel L., Labhasetwar, Vinod, Poptic, Earl J., Forudi, Farhad, Guzman, Luis A., DiCorleto, Paul E., Levy, Robert J., Topol, Eric J., Ellis, Stephen G.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.03.1997; Elsevier
• Subjects: Animals; Biological and medical sciences; Cardiovascular system; Carotid Artery, Common - pathology; Cell Division - drug effects; Cells, Cultured; Disease Models, Animal; Drug Delivery Systems; Male; Medical sciences; Muscle, Smooth - cytology; Nitriles - administration & dosage; Pharmacology. Drug treatments; Phenols - administration & dosage; Polymers; Protein-Tyrosine Kinases - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Tunica Intima - pathology; Tunica Intima - physiology; Tyrphostins; Vascular wall; Cell proliferation; Tyrosine; Rat; Enzyme; Transferases; Treatment efficiency; Rodentia; Instrumentation therapy; Enzyme inhibitor; Smooth muscle; Instrumental dilatation; In vitro; In vivo; Local administration; Vertebrata; Chemotherapy; Mammalia; Treatment; Kinase; Animal; Carotid
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/S0002-8703(97)70228-X

Smooth-muscle cell proliferation in response to arterial injury represents an important etiologic factor in restenosis after angioplasty. Tyrphostin-47, a protein tyrosine kinase inhibitor, inhibits smooth-muscle cell proliferation in vitro. In this study tyrphostin-47 was incorporated into matrixes to determine whether prolonged local delivery would result in a reduction of neointimal proliferation after arterial injury in a rat carotid balloon-injury model. A polymer matrix (polylactic polyglycolic acid copolymer and pluronic gel F-127, mean matrix weight 7.83 ± 0.39 mg) was loaded with tyrphostin-47 (25% w/w). Release studies demonstrated delivery of 11% of the incorporated drug over a 21-day release period. In cell culture, tyrphostin-47 released from the polymer matrix produced a reduction in smooth-muscle cell proliferation ( p < 0.0007). Balloon denudation injury of the left common carotid artery of 34 animals was performed. In 12 animals, polymer matrixes containing tyrphostin-47 were wrapped around the injured arteries to provide prolonged drug delivery (estimated dosage 28 μg/kg/24 hr); in 10 animals a polymer matrix without tyrphostin-47 was implanted; and in 12 animals only balloon injury was performed. The mean neointimal cross-sectional areas, luminal areas, and intima/media ratios were not significantly different among animals receiving local treatment with tyrphostin-47, sham polymer after injury, or balloon injury without polymer implantation. We conclude that despite inhibition of smooth-muscle cell proliferation by tyrphostin-47 in vitro, sustained local delivery of this tyrosine kinase inhibitor does not result in a reduction of neointimal proliferation in the rat carotid injury model. (Am Heart J 1997;133:329-34.)