Power-Up for Mucoadhesiveness: Two Generations of Thiolated Surfactants for Enhanced Sticky Nanoemulsions.

Nanoemulsions can be tuned toward enhanced gastro-intestinal retention time by incorporating thiolated surfactants into their surface. Tailoring the chemical reactivity of the thiol headgroup has major influence on mucoadhesive features of the nanoemulsion. Two generations of thiolated surfactants were synthetically derived from PEG-40-stearate featuring either a free thiol group or an S-protected thiol group. The surfactants were characterized regarding critical micelle concentration (CMC), hemolytic activity, and cytotoxicity. Subsequently, they were incorporated into nanoemulsions and the resulting nanoemulsions were characterized regarding particle size, polydispersity index (PDI), zeta potential, and time-dependent stability. Afterward, mucosal interactions as well as mucoadhesion on porcine intestinal mucosa were investigated. Successful synthesis of Cysteine-PEG-40-stearate (CYS-PEG-40-stearate) and MNA-Cysteine-PEG-40-stearate (MNA-CYS-PEG-40-stearate) was confirmed by 1 H NMR spectroscopy. Both chemical modifications led to slightly elevated CMC values while preserving low cytotoxicity and hemotoxicity. Incorporation into nanoemulsions had minor influence on overall physical particle characteristics, while interactions with mucus and mucoadhesiveness of the nanoemulsions were drastically improved resulting in the rank order PEG-40-stearate < CYS-PEG-40-stearate < MNA-CYS-PEG-40-stearate. Accordingly, thiolated surfactants, especially S-protected derivatives, are versatile tools to generate highly mucoadhesive nanoemulsions.