Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment

Abstract

Catheter-based local delivery of biodegradable nanoparticles (NP) with sustained release characteristics represents a therapeutic approach to reduce restenosis. Paclitaxel-loaded NP consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) (PVA-g-PLGA) with varying PLGA chain length as well as poly(lactide-co-glycolide) (PLGA), were prepared by a solvent evaporation technique. NP of < 180 nm in diameter characterized by photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) are spherical and show smooth surfaces. Yields typically range from 80 to 95% with encapsulation efficiencies between 77 and 87%. The extent of initial in vitro paclitaxel release was affected by the PVA-g-PLGA composition. Blank nanoparticles from PVA 300-g-PLGA(30) and PVA 300-g-PLGA(15) showed excellent biocompatibility in rabbit vascular smooth muscle cells (RbVSMC) at polymer concentrations of 0.37 mg/ml. Paclitaxel-loaded NP have an increased antiproliferative effect on cells in comparison to free drug. Confocal laser scanning microscopy of RbVSMC confirmed cellular uptake of nanoparticles composed of fluorescently labeled PVA 300-g-PLGA(15) loaded with Oregon Green labeled paclitaxel. Cells showed a clearly increased fluorescence activity with a co-localization of paclitaxel and polymer nanoparticles during incubation with particle suspension. To evaluate the antirestenotic effect in vivo, paclitaxel-loaded nanoparticles were administered locally to the wall of balloon-injured rabbit iliac arteries using a porous balloon catheter. As a result a 50% reduction in neointimal area in vessel segments treated with paclitaxel-loaded nanoparticles compared to control vessel segments could be observed (local paclitaxel nanoparticle treated segments 0.80 ± 0.19 mm 2, control segments 1.58 ± 0.6 mm 2; p < 0.05).