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 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 micrograms/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.
Gottsauner-Wolf
M
M
Department of Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, OH 44195, USA.
Jang
Y
Y
Lincoff
A M
AM
Cohen
J L
JL
Labhasetwar
V
V
Poptic
E J
EJ
Forudi
F
F
Guzman
L A
LA
DiCorleto
P E
PE
Levy
R J
RJ
Topol
E J
EJ
Ellis
S G
SG
D000818:Animals; D017536:Carotid Artery, Common / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology*; D009570:Nitriles / Q000008:administration & dosage*; D010636:Phenols / Q000008:administration & dosage*; D011108:Polymers; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology / Q000502:physiology; D020032:Tyrphostins
D009570:Nitriles; D010636:Phenols; D011108:Polymers; D020032:Tyrphostins; C060152:tyrphostin 47; D011505:Protein-Tyrosine Kinases