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

Smooth-muscle cell proliferation in response to arterial injury repres ents an important etiologic factor in restenosis after angioplasty. Ty rphostin-47, a protein tyrosine kinase inhibitor, inhibits smooth-musc le cell proliferation in vitro. In this study tyrphostin-47 was incorp orated into matrixes to determine whether prolonged local delivery wou ld result in a reduction of neointimal proliferation after arterial in jury in a rat carotid balloon-injury model. A polymer matrix (polylact ic polyglycolic acid copolymer and pluronic gel F-127, mean matrix wei ght 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 th e polymer matrix produced a reduction in smooth-muscle cell proliferat ion (p < 0.0007). Balloon denudation injury of the left common carotid artery of 34 animals was performed. In 12 animals, polymer matrixes c ontaining tyrphostin-47 were wrapped around the injured arteries to pr ovide prolonged drug delivery (estimated dosage 28 mu g/kg/24 hr); in 10 animals a polymer matrix without tyrphostin-47 was implanted; and i n 12 animals only balloon injury was performed. The mean neointimal cr oss-sectional areas, luminal areas, and intima/media ratios were not s ignificantly different among animals receiving local treatment with ty rphostin-47, sham polymer after injury, or balloon injury without poly mer implantation. We conclude that despite inhibition of smooth-muscle cell proliferation by tyrphostin-47 in vitro, sustained local deliver y of this tyrosine kinase inhibitor does not result in a reduction of neointimal proliferation in the rat carotid injury model.