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

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.