Aim: The aim of this study was the comparison of the mucoadhesive properties of nonionic, negatively, and positively charged thiolated cyclodextrins (CDs), including α-, β-, and γ-CDs of low and high degree of thiolation.
Methods: Native α-, β-, and γ-CDs were thiolated with phosphorous pentasulfide in sulfolane (CD-SH) (i), via reductive amination with cysteamine after oxidative ring opening (CD-Cya) (ii), and via esterification with mercaptosuccinic acid (CD-MSA) (iii). These thiolated CDs were characterized via 1H NMR and Ellman's test. Cytotoxicity was determined via resazurin and hemolysis assay. Mucoadhesive properties were evaluated via rheological studies with freshly isolated porcine mucus, as well as residence time studies on porcine small intestinal mucosa.
Results: The structure of thiolated CDs was confirmed via 1H NMR. The degree of thiolation was in the range of 594-1034 µmol/g for low and 1360-3379 µmol/g for high CD-SH, whereas thiolated CD-Cya and thiolated CD-MSA exhibited a degree of thiolation of 1142-3242 µmol/g and 243-1227 µmol/g, respectively. Just cationic CDs showed cytotoxicity. Nonionic highly thiolated α-CD-SH, α-CD-Cya, and α-CD-MSA exhibited with mucus 5.6-, 15.7- and 2.8-fold improved dynamic viscosity, while improvement was 7.7-, 6.1-, and 5.4-fold for the corresponding thiolated β-CDs and 12.3-, 15.4- and 17.8-fold for the corresponding thiolated γ-CDs compared with native CDs, respectively. A prolonged mucosal residence time following the rank order γ > β > α was observed for all thiolated CDs, whereby γ-CD-Cya, nonionic highly thiolated β-CD-SH and α-CD-Cya showed the highest mucoadhesive properties.
Conclusion: A high degree of thiolation and the introduction of cationic charges are mainly responsible for high mucoadhesive properties of CDs.
Keywords: Cyclodextrins; Mucoadhesion; Mucosal residence time; Thiolated cyclodextrins; Thiomers.
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