Hydrocaffeic acid-chitosan nanoparticles with enhanced stability, mucoadhesion and permeation properties

Catechol-containing molecules, such as hydrocaffeic acid (HCA) have been shown to increase the mucoadhesion of several polymers. We report here a simple and bioinspired approach to enhance chitosan (CS) mucoadhesion and stabilize it in nanoparticulate form by preparing HCA-CS conjugates. HCA-CS conjugates containing 6 and 15mol% HCA were synthesized and characterized by FT-IR, (1)H NMR and UV-vis spectrophotometry. HCA-CS nanoparticles prepared by ionic gelation with sodium tripolyphosphate (TPP) ranged in size between 100 and 250nm depending on the polymer and TPP/CS weight ratio. In contrast to CS nanoparticles, which aggregate at pH>6.5, HCA-CS nanoparticles did not show any sign of aggregation or precipitation over the 4-10 pH range and maintain their size. Unexpectedly, HCA-CS nanoparticles also maintained their size and polydispersity index at pH 7.4 and NaCl concentrations of up to 500mM. Partial oxidation of HCA resulted in nanoparticle cross-linking and improved stability at pH<4. HCA-CS mucoadhesion to rabbit small intestine was 6 times higher than unmodified CS. CS and HCA-CS nanoparticles were able to induce reversible tight junction opening in Caco-2 cell monolayers. Tight junction opening facilitated the permeability of a model hydrophilic molecule, fluorescein isothiocyanate-labeled dextran (FD4) and was 3 times higher in the cells treated with HCA-CS 15% nanoparticles compared to control groups. HCA-CS conjugates were found to be excellent candidates for stable nanodelivery systems with enhanced oral absorption of hydrophilic molecules.