Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis.
Restenosis, the principal complication of percutaneous transluminal coronary angioplasty is responsible for the 35-40% long-term failure rate following coronary revascularization. The neointimal formation, a morphological substrate of restenosis, is dependent on smooth muscle cells (SMC) proliferation and migration. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptors system is involved in the process of post-angioplasty restenosis. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the release kinetics and in vivo effects of nanoparticles containing PDGF-Receptor beta (PDGFRbeta) tyrphostin inhibitor, AG-1295. AG-1295-loaded poly(DL-lactide) (PLA) nanoparticles were prepared by spontaneous emulsification/solvent displacement technique. In vitro release rate and the impact of drug/polymer ratio on the nanoparticle size were determined. The degree of tyrosine phosphorylation was assessed by Western blot with phosphotyrosine-specific antibody in rat SMC extracts. Several bands characteristic of PDGF BB-stimulated SMC disappeared or weakened following tyrphostin treatment. Local intraluminal delivery of AG-1295-loaded PLA nanoparticles to the injured rat carotid artery had no effect on proliferative activity in medial and neointimal compartments of angioplastisized arteries, indicating a primary antimigration effect of AG-1295 on medial SMC.
Fishbein
I
I
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem, Israel.
Chorny
M
M
Rabinovich
L
L
Banai
S
S
Gati
I
I
Golomb
G
G
D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D008297:Male; D008856:Microscopy, Fluorescence; D008863:Microspheres; D010316:Particle Size; D010982:Platelet-Derived Growth Factor; D051381:Rats; D014018:Tissue Distribution; D020032:Tyrphostins / Q000008:administration & dosage* / Q000493:pharmacokinetics
C407689:6,7-dimethoxy-2-phenylquinoxaline; D010982:Platelet-Derived Growth Factor; D020032:Tyrphostins