Biocompatibility study of quaternized chitosan on the proliferation and differentiation of Caco-2 cells as an in vitro model of the intestinal barrier

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The development of different chitosan derivatives for medical applications has increased recently. Among these chitosan derivatives, quaternized chitosan was designed to improve the solubility of chitosan in biological fluids for oral drug delivery while retaining the cationic character for mucoadhesion. However, the biocompatibility of quaternized chitosan on the human intestine is unknown. In this study, we aimed to examine the potential biological effects of quaternized chitosan on the intestinal barrier, in terms of cell proliferation and cell differentiation, using the Caco-2 cell line as an in vitro model. The lower the degree of substitution of quaternized chitosan, the lower the cytotoxic and anti-proliferative effect on Caco-2 cells. In addition, the anti-proliferative effect of quaternized chitosan might induce a cell cycle disturbance and differentiation delay. Long-term continuous exposure (9 days) to quaternized chitosan caused a delay in differentiation of the Caco-2 cells even at non-cytotoxic quaternized chitosan doses (0.005% (w/v)), as shown by the low level of alkaline phosphatase in the quaternized chitosan–treated group compared to the control cells. In contrast, short-term discontinuous exposure to quaternized chitosan (0.005% (w/v) for 4 h/day over 9 days) that more realistically mimics the daily intestinal exposure did not inhibit the intestinal differentiation of Caco-2 cells. Thus, the use of a low degree of substitution and a low concentration of quaternized chitosan resulted in a good biocompatibility to the intestinal barrier supporting the potential usefulness of quaternized chitosan in the application of an oral drug delivery system.