Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers

N-Trimethyl chitosan chloride (TMC) is a permanently quaternized chitosan d erivative with improved aqueous solubility compared to native chitosan. TMC is able to open the tight junctions of intestinal epithelia at physiologic al pH values, where chitosan is insoluble and therefore ineffective. TMCs w ith degrees of substitution of 40 and 60% were synthesized according to a n ovel synthesis procedure and their effect on the permeability of the tight junctions of the intestinal Caco-2 monolayers was studied, measuring the tr ansepithelial electrical resistance and the transport of a mainly paracellu larly transported compound, [C-14]-mannitol. Toxicity studies using nucleic stains were done to establish the transport as a cause of opening of the t ight junctions and not of possible cytotoxicity. TMC60 showed higher transp ort enhancement ratios than TMC40 in all concentrations tested (0.05-1.0%, w/.v). Both derivatives did not affect the viability of the Caco-2 cell mon olayers. These results suggest that high charge density is necessary for TM C to substantially improve the paracellular permeability of intestinal epit helia. It is expected that TMC40 and TMC60 will enhance the intestinal perm eation of hydrophilic macromolecular drugs such as peptides and proteins. ( C) 2000 Elsevier Science B.V. All rights reserved.