caa a22 4500 477126332 CHVBK 20180405111650.0 cr unu---uuuuu 170330e19970701xx s 000 0 eng 10.1023/A:1012160102740 doi (NATIONALLICENCE)springer-10.1023/A:1012160102740 Chitosans as Absorption Enhancers for Poorly Absorbable Drugs 2: Mechanism of Absorption Enhancement [Elektronische Daten] [Nicolaas Schipper, Susanne Olsson, Janet Hoogstraate, Albertus deBoer, Kjell Vårum, Per Artursson] Purpose. It has recently been shown that the absorption enhancing and toxic effects of chitosans are dependent on their chemical composition. In this study, the mechanisms underlying these effects were investigated at the cellular level. Methods. The effects on epithelial cells of chitosans with different chemical composition, absorption enhancing properties and toxicities were studied in Caco-2 monolayers. Chitosan C(l:31) has a low degree of acetylation (DA) (1%) and a low m.w. (31 kD), and displays dose-dependent absorption enhancement and cytotoxicity; chitosan C(35:170) has a higher DA (35%) and a higher m.w. (170 kD), is less dose-dependent in absorption enhancement, and is not cytotoxic. A third non-toxic chitosan C(49:22) with a high DA (49%), a low m.w. (22 kD), and no influence on epithelial permeability was used as control. Results. C(l:31) and C(35:170) bound tightly to the epithelium. Cellular uptake of the chitosans was not observed. Both chitosans increased apical but not basolateral cell membrane permeability and induced a redistribution of cytoskeletal F-actin and the tight junction protein ZO-1. This resulted in increased paracellular permeability of hydrophilic marker molecules of different molecular weights. Addition of negatively charged heparin inhibited the cellular and the absorption enhancing effects of the chitosans, indicating that these effects are mediated via their positive charges. The onset of the effects of C(35:170) on apical membrane permeability and tight junction structure was much faster than that of C(l:31). C(49:22) did not influence any of the properties of the Caco-2 cell monolayers studied. Conclusions. The binding and absorption enhancing effects of chitosans on epithelial cells are mediated through their positive charges. The interaction of chitosans with the cell membrane results in a structural reorganisation of tight junction-associated proteins which is followed by enhanced transport through the paracellular pathway. Plenum Publishing Corporation, 1997 chitosan nationallicence Caco-2 nationallicence absorption enhancer nationallicence drug transport nationallicence drug absorption nationallicence tight junction nationallicence epithelial permeability nationallicence Schipper Nicolaas Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut Olsson Susanne Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut Hoogstraate Janet LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut deBoer Albertus LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut Vårum Kjell Norwegian Biopolymer Laboratory (NOBIPOL), Dept. of Biotechnology, The Norwegian University of Science and Technology, 7034, Trondheim, Norway aut Artursson Per Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 923-929 0724-8741 14:7<923 1997 14 11095 https://doi.org/10.1023/A:1012160102740 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012160102740 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Schipper Nicolaas Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut NATIONALLICENCE 700 1- Olsson Susanne Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut NATIONALLICENCE 700 1- Hoogstraate Janet LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut NATIONALLICENCE 700 1- deBoer Albertus LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Vårum Kjell Norwegian Biopolymer Laboratory (NOBIPOL), Dept. of Biotechnology, The Norwegian University of Science and Technology, 7034, Trondheim, Norway aut NATIONALLICENCE 700 1- Artursson Per Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 923-929 0724-8741 14:7<923 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer