The tyrphostin AG1295, a selective blocker of PDGF-receptor kinase, exerts a marked inhibitory effect on the activation, migration, and proliferation of porcine and human SMCs in vitro and an approximately 50% inhibitory effect on neointimal formation after balloon injury in porcine femoral arteries when delivered via biodegradable nanoparticles. Further studies appear to be warranted to evaluate the applicability of this novel approach to the interventional setting.
Local implantation or injection of microspheres containing bisphosphonates for site-specific therapy may aid in treating several pathological conditions associated with bone destruction. Chitosan microspheres containing two antiresorption and anticalcification agents, pamidronate and suberoylbisphosphonate (SuBP), were prepared from a w/o emulsion. Various formulation variables were studied for their effect on the release rate profile of these bone-seeking agents. Polymer coating of micromatrices yielded microspheres with the most retarded release rate, and the drug delivery system was found biocompatible in endothelial cell culture. The microspheres were examined in vitro and in vivo for release kinetics and drug disposition. The release of bisphosphonate from the microspheres was faster in vitro than in vivo. Drug disposition following implantation of microspheres in the tibialis muscle resulted in a relatively increased disposition in the adjacent tibia while injection of drug solution in the tibialis muscle resulted in uniform disposition of the drug in the femorae and tibiae. Bisphosphonate released from chitosan microspheres effectively inhibited bioprosthetic tissue calcification in the rat subdermal model.
Abstract-Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) system is involved in the process of postangioplasty restenosis. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the antiproliferative effects of PDGFR-specific tyrphostin AG-1295 in vitro and in vivo. AG-1295 significantly inhibited rat smooth muscle cell growth stimulated by PDGF-BB or FCS. This antiproliferative effect was paralleled by reversible reduction of the total phosphotyrosine level and the degree of PDGFR phosphorylation by the drug in vitro. Local sustained delivery of the drug from perivascularly implanted polymeric matrices resulted in focal AG-1295 levels of 711 and 29.1 ng/mg of dry arterial tissue 1 and 14 days after implantation in rats. AG-1295 delivered from polymeric matrices resulted in a 35% reduction of neointimal formation on day 14 after balloon injury in the rat carotid model. Tyrosine phosphorylation of certain transduction proteins in arterial tissue extracts was significantly upregulated by balloon injury on day 3 but was essentially returned to or below basal levels 14 days after injury. Tyrphostin treatment decreased tyrosine phosphorylation at both time points below the basal levels. Moreover, the enhancement of PDGFR expression 3 and 14 days after arterial injury was strongly inhibited by AG-1295 treatment. It can be concluded that AG-1295 reduces neointimal formation by inhibiting PDGF-triggered tyrosine phosphorylation.
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