Nasal delivery of antisense oligonucleotides: in vitro evaluation of a thiomer/glutathione microparticulate delivery system.

摘要

PURPOSE: The aim of this study was to develop a nasal mucoadhesive microparticulate delivery system for phosphorothioate antisense oligonucleotides (PTO-ODNs) utilizing the thiomer technology. METHODS: PTO-ODN microparticles, coated with either the mucoadhesive polymer polycarbophil-cysteine (PCP-Cys) or unmodified PCP and reduced glutathione (GSH) were prepared by the emulsification solvent evaporation technique. Particle size, drug load, decrease in thiol groups on microparticles, swelling properties, release of incorporated PTO-ODN, and mucoadhesive properties were examined. Permeation enhancing effect of the deployed thiomer conjugate was investigated on excised porcine respiratory mucosa of the nasal cavity. RESULTS: Results demonstrated that microparticles were almost of spherical structure displaying particle diameter up to 30 microm. In addition, a controlled drug release of the incorporated PTO-ODN was achieved from these particles. Mucoadhesion studies revealed that thiolated PCP-Cys microparticles display 3-fold higher mucoadhesive properties than the corresponding unthiolated polycarbophil microparticles. The uptake of PTO-ODN, incubated in thiolated polycarbophil and glutathione microparticles, from the nasal mucosa was 2.2-fold improved. CONCLUSIONS: According to these results, the thiolated polycarbophil/reduced GSH microparticles might be a promising formulation for systemic delivery of PTO-ODNs via the nasal route.