| 초록 |
Mucosal administration of macromolecules such as plasmid DNA and protein is emerging as a new route of delivery for therapeutic genes and vaccines. To develop more potent and convenient mucosal delivery system, we designed delivery vehicles composed of in situ gelling and mucoadhesive polymers. Poloxamers (Pol) were used to provide in situ gelling property and polycarbophil (PC) or polyethylene oxide (PEO) was used as mucoadhesive polymer. The gelation temperatures of the gels slightly decreased by the mucoadhesive polymers, but not by plasmid DNA and protein. The in vitro release of plasmid DNA from the gels followed Fickian diffusion. The absorption of plasmid DNA varied with the contents and type of mucoadhesive polymers. Of vehicles, Pol/PC 0.2% showed the highest absorption with an AUC value 11-fold higher than saline. The nasal retention of plasmid DNA was highly prolonged by mucoadhesive polymers. The histopathology of nasal tissues was not altered after repeated dosing over 2 weeks. In addition, the Pol/PC gels containing HBsAg as a model protein also showed the prolonged retention at the vaginal tissues. The in situ-gelling mucoadhesive HBsAg delivery system enhanced the mucosal and systemic immune responses. Moreover, as another vaccine vehicle, the Pol/PEO gels induced the vaginal and salivary immune responses to HPV 16 L1 VLP intravaginally administered into mice. At 6 weeks after the first intravaginal immunization of HPV 16 L1 VLP with cholera toxin, vaginal and salivary IgA titers were the highest in the group given in Pol/PEO 1.0% vehicle followed by Pol/PEO 0.4% and PBS vehicles. Following intravaginal administration, Pol/PEO 1.0%, but not Pol/PEO 0.4%, showed significantly higher HPV 16 L1 VLP-specific serum IgG titers as compared to the PBS vehicle. These results indicate that the use of in situ-gelling mucoadhesive delivery systems would be beneficial for mucosal delivery of bioactive macromolecules and induction of mucosal and systemic immune responses without toxicity. |
