Drug-eluting stent coatings for the treatment of bronchotracheal cancer

Abstract

One of the complications of bronchotracheal cancer is obstruction of the upper airways. Local tumor resection in combination with an airway stent can suppress intraluminal tumor (re)growth. We have investigated a novel PulmoStent for local release of the anticancer drug gefitinib. We evaluated different types of polymeric covers for a tissue engineered airway stent. The distinguishing feature of this stent concept is that respiratory epithelial cells can grow on the luminal surface of the stent which facilitates mucociliary clearance. To facilitate growth of epithelial cells at the air-liquid interface of the stent, we developed a polyurethane cover that allows transport of nutrients to the cells. Nonwoven polycarbonateurethane(PCU) covers were prepared by a spraying process and evaluated for their porosity and glucose permeability. Respiratory epithelial cells harvested from sheep trachea were cultured onto the selected PCU cover and remained viable at the air-liquid interface when cultured for 21 days. Lastly, we evaluated the radial force of a PCU-covered nitinol stent, and showed the PCU covers didnot adversely affect the mechanical properties of the stents for their intended application in the smaller bronchi. These in vitro data corroborate the design of a novel airway stent for palliative treatment of bronchotracheal stenosis by combination of stent-technology with tissue engineered epithelial cells. Gefitinib-loaded PLGA-based microspheres were prepared using an oil-in-water solvent evaporation method and wet-sieved to obtain well-defined size fractions of 5 ± 1, 32 ± 4, 70 ± 3 and 130 ± 7 μm, respectively. we showed that different size-fractions of drug-loaded microspheres showed quite distinct drug loading and release kinetics. Control of microparticle size by fractionation is therefore an important determinant for obtaining well-defined and reproducible sustained release depots. A polyurethane(PU) sandwich construct was prepared by a spray coating method in which gefitinib was embedded between a PU support layer of 200 μm and a PU top layer of 50-200 μm. The thickness of the PU layer controlled directional release of the drug towards the support layer. PU constructs loaded with gefitinib microspheres released the drug in a sustained manner for more than 6 months indicating that drug release from the microspheres became the rate limiting step. Gefitinib-loaded polyurethane(PU) foams were prepared by embedding either gefitinib micronized crystals or gefitinib-loaded PLGA microspheres in water-blown films, with up to 10% w/w loading for gefitinib microcrystals and 15% w/w for gefitinib microspheres. Drug-release studies showed sustained release of gefitinib over a period of nine months, with higher absolute release rates at higher drug loading content. The suitability of the novel Pulmostent interms of biocompatibility, migration behavior and formation of granulation tissue was investigated in sheep. The results showed that there was only mild granulation tissue formation and tissue reaction; while severe mucus plugging was not observed. Thus, the Pulmostent concept is a step forward for palliative treatment of airway stenosis with a biohybrid stent device.