Comparative study of thiolated and alkenylated functionalized β-CDs as highly mucopenetrating and mucoadhesive drug delivery systems

Within this study, thiolated and alkenylated β-cyclodextrins were developed as novel mucoadhesive excipients capable of interacting with mucosal surfaces and prolonging the residence time of incorporated drugs at absorption sites, thereby potentially enhancing their bioavailability. For this purpose, cysteine-, cysteamine-, allylcarbamate-, and methacrylate-functionalized oligosaccharides were synthesized, and the resulting structures were identified by ¹H NMR spectroscopy, Ellman's and disulfide bond tests, and iodometry. The thiol and double bond content, as well as the stability of these functional groups at 37 °C, over 4 h, were evaluated. Alkenylated β-cyclodextrins showed significantly higher stability in aqueous solution compared to the thiolated products with oxidative sensitivity. Furthermore, the cytotoxicity and rheological, mucodiffusive, and mucoadhesive properties of the derivatives were assessed to elucidate their potential as multifunctional excipients for mucosal drug delivery. The cytotoxicity study confirmed that all derivatives were non-toxic within 4 h of incubation. Rheological measurements showed that β-CD highly modified with allylcarbamate exhibited a 15-fold increase in dynamic viscosity after incubating with intestinal mucus compared to the native β-CD. Regarding mucopenetration, β-CD cysteine was able to penetrate the mucus by more than 3% per 5 cm in 24 h. The results on porcine intestine revealed the superiority of thiolated derivatives in mucoadhesion, with at least 98% of the samples remaining on the intestinal tissue after 3 h of rinsing. For alkenylated β-CD with a similar degree of modification, low mucoadhesiveness was detected, but it was increased significantly with the degree of modification. The current study compares various mucoadhesive approaches and demonstrates that thiolated derivatives are more effective than alkenylated derivatives for mucosal drug delivery, but are less stable in physiological fluids.