Tetradeca-thiolated cyclodextrins: Highly mucoadhesive and in-situ gelling oligomers with prolonged mucosal adhesion

The purpose of this study was to synthesize a highly mucoadhesive tetradeca-thiolated beta-cyclodextrin (5-CD) by replacement of all primary -OH groups at C-6 position and all secondary -OH groups at C-2 position of beta-CD backbone via -SH groups and to evaluate its rheological and mucoadhesive properties in-vitro. Primary and secondary -OH groups of beta-CD were substituted by -SH groups using a microwave-assisted method. The structure of tetradeca-thiolated beta-CD was confirmed by FTIR and H-1 NMR spectroscopy. The modified beta-CD was evaluated for -SH content, thiol stability towards oxidation and cytotoxicity. Moreover, the viscoelastic behavior of the modified oligomer was investigated via rheological studies with porcine intestinal mucus and fibrous structural protein keratin, whereas mucoadhesive properties were evaluated using different porcine mucosae. Tetradeca-thiolated beta-CD oligomer displayed 8144 +/- 317 mu mol thiol groups per gram. These thiol groups displaying a pKa value of 8.2 were stable at pH 4 but prone to oxidation at higher pH values. The newly synthesized thiolated CD did not show any cytotoxicity to Caco-2 cells at a concentration of 0.5% (m/v) within 24 h. Due to the addition of 0.5 and 2% (m/v) tetradeca-thiolated beta-CD to mucus and keratin, the dynamic viscosity was increased up to 7.6- and 5.9- fold, respectively, within 4 h at 37 degrees C. Moreover, in-vitro mucoadhesion studies of tetradeca-thiolated CD showed 78.6-, 60.3-, 62.3- and 49.3- fold improved mucoadhesion on intestinal, buccal, bladder and vaginal mucosa as compared to unmodified beta-CD, respectively. According to these results, tetradeca-thiolated beta-CD might be a promising auxiliary agent to provide a prolonged residence time of drug delivery systems on different mucosal surfaces.