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The present study focused on in vitro release of polylactide-nanoencapsulated tyrphostin AG-1295, a potential agent for local therapy of restenosis. The drug was formulated in matrix-type nanoparticles, termed nanospheres (NS) using the nanoprecipitation method. AG-1295 is a model for low-molecular weight lipophilic compounds, the release behavior of which cannot be adequately characterized by existing methods. An in vitro release technique suitable for optimizing the nanoparticulate formulation release behavior was developed through a novel external sink method and an in situ release method utilizing the environmental sensitivity of the AG-1295 fluorescence spectrum. Similar tendencies were demonstrated by both methods in drug release studied as a function of selected NS preparation variables. The release properties of the drug fractions varying in their binding mode to the carrier particles were studied by the external sink method. The NS surface-adsorbed drug exhibited a significantly higher release rate compared to the drug entrapped in the polymeric matrix. The in situ release of the encapsulated drug was analyzed using the diffusion models of release from a matrix-type sphere. The release was shown to be a composite process, with a burst phase attributed largely to the rapid dissociation of the surface-bound AG-1295. The diffusion-controlled phase exhibited an alteration in kinetic pattern obviously due to the drug distribution between polymeric matrix compartments differing in their permeability. Drug in vitro release investigation may be effectively used to characterize the drug-carrier interaction and internal carrier structure in nanoparticulate formulations, as well as optimize the release behavior in respect to their therapeutic application.

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.