Mitigating Mucoadhesion of β-Cyclodextrins via PEGylation: Insights from ¹⁹F Diffusion NMR Analysis

β-Cyclodextrin (β-CD)-based materials are widely used in drug delivery, yet their interactions with mucosal barriers remain insufficiently understood. Because the mucus layer coating epithelial surfaces can hinder drug transport, elucidating β-CD-mucin interactions is critical for optimizing cyclodextrin-based carriers. In this study, we examined whether PEGylation can attenuate the mucoadhesive behavior of β-CD. Monomethoxy poly(ethylene glycol)-modified β-CDs (MPEG-β-CDs) were evaluated using ¹⁹F self-diffusion NMR spectroscopy coupled with a kinetic diffusion model describing reversible binding to stationary substrates. Mucin hydrogels were prepared from bovine submaxillary mucin and served as a model mucus environment. Diffusion coefficients were extracted from the ¹⁹F NMR signals of 1-fluoroadamantane (1FA) molecules encapsulated within HP-β-CD or MPEG-β-CD cavities. The results demonstrate that PEGylation substantially reduces β-CD-mucin adhesion, with longer PEG chains (2000 Da) providing more effective steric shielding than shorter chains (500 Da). These findings indicate that PEGylation can protect β-CD-included drugs during transport across mucosal barriers by minimizing unwanted β-CD-mucin interactions.