Challenges in evaluation of chitosan and trimethylated chitosan (TMC) as mucosal permeation enhancers: From synthesis to in vitro application

Journal of Controlled Release

Volumn 173, Issue , 2014, Pages 18-31

  Benediktsdóttir, Berglind Eva ^a   Baldursson, Ólafur ^b   Másson, Már ^a  

^a UNIVERSITY OF ICELAND   (Iceland)

^b LANDSPITALI UNIVERSITY HOSPITAL   (Iceland)

Author keywords

Chitosan; Drug delivery; Structure elucidation; Tight junction; TMC; Trimethylation

Indexed keywords

ALKYLATION; CHITOSAN; DRUG DELIVERY;

EXPERIMENTAL CONDITIONS; POLYSACCHARIDE CHITOSAN; STRUCTURAL CHARACTERIZATION; STRUCTURE ELUCIDATION; TIGHT JUNCTIONS; TRIMETHYLATED CHITOSANS; TRIMETHYLATION; WATER-SOLUBLE CHITOSAN; STRUCTURE ACTIVITY RELATIONSHIPS; TMC;

CHITIN; CHITOSAN;

CHITOSAN DERIVATIVE; PENETRATION ENHANCING AGENT; TRIMETHYLATED CHITOSAN; UNCLASSIFIED DRUG; CHITOSAN; MANNITOL; OCTREOTIDE;

AIRWAY DELIVERY; AIRWAY EPITHELIAL CELL; CACO 2 CELL LINE; CELL MEMBRANE PERMEABILITY; CELL VIABILITY; DRUG DELIVERY SYSTEM; DRUG MECHANISM; GASTRIC MUCOSA; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTESTINAL DELIVERY; METHYLATION; PRIORITY JOURNAL; REVIEW; STRUCTURE ACTIVITY RELATION; SYNTHESIS; ACETYLATION; ACUTE TOXICITY; ARTICLE; BIOCOMPATIBILITY; BIODEGRADABILITY; BRONCHUS MUCOSA; CANCER CELL CULTURE; CARBON NUCLEAR MAGNETIC RESONANCE; CELL DIFFERENTIATION; CELL LINE; CYTOTOXICITY; DEACETYLATION; DIET SUPPLEMENTATION; DRUG ABSORPTION; DRUG PENETRATION; DRUG SOLUBILITY; EPITHELIUM CELL; GASTROINTESTINAL TRACT; HETERONUCLEAR SINGLE QUANTUM COHERENCE; INTERNALIZATION; INTRACELLULAR SIGNALING; MACROPHAGE; NONHUMAN; POTENTIOMETRY; PROTEIN EXPRESSION; PROTON NUCLEAR MAGNETIC RESONANCE; TIGHT JUNCTION; WEIGHT CONTROL;

ANIMALS; CHITOSAN; DRUG CARRIERS; HUMANS; INTESTINAL MUCOSA; RESPIRATORY MUCOSA;

EID: 84888191252     PISSN: 01683659     EISSN: 18734995     Source Type: Journal    
DOI: 10.1016/j.jconrel.2013.10.022     Document Type: Review

References (127)

1. [1] Medicines in Development: Biotechnology, Pharmaceutical Research and Manufacturers of America. Available from http://www.phrma.org/sites/default/files/1776/biotech2011.pdf, 2011 (Accessed on: August 24, 2012).
2. [2] Baldrick, P., The safety of chitosan as a pharmaceutical excipient. Regul. Toxicol. Pharmacol. 56 (2010), 290–299.
3. [3] Lehr, C.M., Bouwstra, J.A., Schacht, E.H., Junginger, H.E., In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm. 78 (1992), 43–48.
4. [4] Kurita, K., Chitin and chitosan: functional biopolymers from marine crustaceans. Mar. Biotechnol. 8 (2006), 203–226.
5. [5] Anthonsen, M.W., Smidsrod, O., Hydrogen-ion titration of chitosans with varying degrees of N-acetylation by monitoring induced H-1-Nmr chemical-shifts. Carbohydr. Polym. 26 (1995), 303–305.
6. [6] Muzzarelli, R.A.A., Human enzymatic activities related to the therapeutic administration of chitin derivatives. Cell. Mol. Life Sci. 53 (1997), 131–140.
7. [7] Vårum, K.M., Myhr, M.M., Hjerde, R.J.N., Smidsrød, O., In vitro degradation rates of partially N-acetylated chitosans in human serum. Carbohydr. Res. 299 (1997), 99–101.
8. [8] Verheul, R.J., Amidi, M., van Steenbergen, M.J., van Riet, E., Jiskoot, W., Hennink, W.E., Influence of the degree of acetylation on the enzymatic degradation and in vitro biological properties of trimethylated chitosans. Biomaterials 30 (2009), 3129–3135.
9. [9] Merkel, O.M., Zheng, M., Debus, H., Kissel, T., Pulmonary gene delivery using polymeric nonviral vectors. Bioconjug. Chem. 23 (2012), 3–20.
10. [10] Illum, L., Jabbal-Gill, I., Hinchcliffe, M., Fisher, A.N., Davis, S.S., Chitosan as a novel nasal delivery system for vaccines. Adv. Drug Deliv. Rev. 51 (2001), 81–96.
11. [11] Kong, M., Chen, X.G., Xing, K., Park, H.J., Antimicrobial properties of chitosan and mode of action: a state of the art review. Int. J. Food Microbiol. 144 (2010), 51–63.
12. [12] Artursson, P., Lindmark, T., Davis, S.S., Illum, L., Effect of chitosan on the permeability of monolayers of intestinal epithelial-cells (Caco-2). Pharm. Res. 11 (1994), 1358–1361.
13. [13] Muzzarelli, R.A.A., Greco, F., Busilacchi, A., Sollazzo, V., Gigante, A., Chitosan, hyaluronan and chondroitin sulfate in tissue engineering for cartilage regeneration: a review. Carbohydr. Polym. 89 (2012), 723–739.
14. [14] Mathews, S., Gupta, P.K., Bhonde, R., Totey, S., Chitosan enhances mineralization during osteoblast differentiation of human bone marrow-derived mesenchymal stem cells, by upregulating the associated genes. Cell Prolif. 44 (2011), 537–549.
15. [15] Wedmore, I., McManus, J.G., Pusateri, A.E., Holcomb, J.B., A special report on the chitosan-based hemostatic dressing: experience in current combat operations. J. Trauma 60 (2006), 655–658.
16. [16] Schiller, R.N., Barrager, E., Schauss, A.G., Nichols, E.J., A randomized, double-blind, placebo-controlled study examining the effects of a rapidly soluble chitosan dietary supplement on weight loss and body composition in overweight and mildly obese individuals. J. Am. Nutraceutical Assoc. 4 (2001), 42–49.
17. [17] CDER/FDA, Guidance for industry: Waiver of in vivo bioavailability and bioequivalance studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf, 2000 (Accessed on: February 5, 2013).
18. [18] EMEA, Note for guidance on the investigation of bioavailability and bioequivalence. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003519.pdf, 2000 (Accessed on: February 6, 2013).
19. [19] Schneeberger, E.E., Lynch, R.D., The tight junction: a multifunctional complex. Am. J. Physiol. Cell Physiol. 286 (2004), C1213–C1228.
20. [20] Watson, C.J., Rowland, M., Warhurst, G., Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am. J. Physiol. Cell Physiol. 281 (2001), C388–C397.
21. [21] Tang, V.W., Goodenough, D.A., Paracellular ion channel at the tight junction. Biophys. J. 84 (2003), 1660–1673.
22. [22] Yu, A.S.L., Enck, A.H., Lencer, W.I., Schneeberger, E.E., Claudin-8 expression in Madin-Darby canine kidney cells augments the paracellular barrier to cation permeation. J. Biol. Chem. 278 (2003), 17350–17359.
23. [23] Lu, S., Gough, A.W., Bobrowski, W.F., Stewart, B.H., Transport properties are not altered across Caco-2 cells with heightened TEER despite underlying physiological and ultrastructural changes. J. Pharm. Sci. 85 (1996), 270–273.
24. [24] Yee, S.Y., In vitro permeability across Caco3 cells (colonic) can predict in vivo (small intestinal) absorption in man — fact or myth. Pharm. Res. 14 (1997), 763–766.
25. [25] Cell culture models of biological barriers. In vitro Test Systems for Drug Absorption and Delivery, 2002, Taylor & Francis.
26. [26] Fogh, J., Fogh, J.M., Orfeo, T., 127 cultured human tumor-cell lines producing tumors in nude mice. J. Natl. Cancer Inst. 59 (1977), 221–226.
27. [27] Artursson, P., Epithelial Transport of drugs in cell-culture.1. A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J. Pharm. Sci. 79 (1990), 476–482.
28. [28] Marino, A.M., Yarde, M., Patel, H., Chong, S., Balimane, P.V., Validation of the 96 well Caco-2 cell culture model for high throughput permeability assessment of discovery compounds. Int. J. Pharm. 297 (2005), 235–241.
29. [29] Vllasaliu, D., Casettari, L., Fowler, R., Exposito-Harris, R., Garnett, M., Illum, L., Stolnik, S., Absorption-promoting effects of chitosan in airway and intestinal cell lines: a comparative study. Int. J. Pharm. 430 (2012), 151–160.
30. [30] Kudsiova, L., Lawrence, M.J., A comparison of the effect of chitosan and chitosan-coated vesicles on monolayer integrity and permeability across Caco-2 and 16HBE14o-cells. J. Pharm. Sci. 97 (2008), 3998–4010.
31. [31] Artursson, P., Karlsson, J., Correlation between oral-drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) Cells. Biochem. Biophys. Res. Commun. 175 (1991), 880–885.
32. [32] Tavelin, S., Milovic, V., Ocklind, G., Olsson, S., Artursson, P., A conditionally immortalized epithelial cell line for studies of intestinal drug transport. J. Pharmacol. Exp. Ther. 290 (1999), 1212–1221.
33. [33] Grasset, E., Pinto, M., Dussaulx, E., Zweibaum, A., Desjeux, J.F., Epithelial properties of human colonic-carcinoma cell-line Caco-2 — electrical parameters. Am. J. Physiol. 247 (1984), C260–C267.
34. [34] Press, B., Di Grandi, D., Permeability for intestinal absorption: Caco-2 assay and related issues. Curr. Drug Metab. 9 (2008), 893–900.
35. [35] Jones, C.F., Grainger, D.W., In vitro assessments of nanomaterial toxicity. Adv. Drug Deliv. Rev. 61 (2009), 438–456.
36. [36] Cozens, A.L., Yezzi, M.J., Kunzelmann, K., Ohrui, T., Chin, L., Eng, K., Finkbeiner, W.E., Widdicombe, J.H., Gruenert, D.C., CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 10 (1994), 38–47.
37. [37] Shen, B.Q., Finkbeiner, W.E., Wine, J.J., Mrsny, R.J., Widdicombe, J.H., Calu-3: a human airway epithelial cell line that shows cAMP-dependent Cl-secretion. Am. J. Physiol. Lung Cell. Mol. Physiol. 266 (1994), L493–L501.
38. [38] Wan, H., Winton, H., Soeller, C., Stewart, G., Thompson, P., Gruenert, D., Cannell, M., Garrod, D., Robinson, C., Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HBE14o. Eur. Respir. J. 15 (2000), 1058–1068.
39. [39] Manford, F., Tronde, A., Jeppsson, A.-B., Patel, N., Johansson, F., Forbes, B., Drug permeability in 16HBE14o-airway cell layers correlates with absorption from the isolated perfused rat lung. Eur. J. Pharm. Sci. 26 (2005), 414–420.
40. [40] Mathias, N.R., Timoszyk, J., Stetsko, P.I., Megill, J.R., Smith, R.L., Wall, D.A., Permeability characteristics of Calu-3 human bronchial epithelial cells: In vitro-in vivo correlation to predict lung absorption in rats. J. Drug Target. 10 (2002), 31–40.
41. [41] Halldorsson, S., Asgrimsson, V., Axelsson, I., Gudmundsson, G.H., Steinarsdottir, M., Baldursson, O., Gudjonsson, T., Differentiation potential of a basal epithelial cell line established from human bronchial explant. In Vitro Cell. Dev. Biol. Anim. 43 (2007), 283–289.
42. [42] Benediktsdottir, B.E., Arason, A.J., Halldórsson, S., Gudjónsson, T., Masson, M., Baldursson, Ó., Drug delivery characteristics of the progenitor bronchial epithelial cell line VA10. Pharm. Res. 30 (2013), 781–791.
43. [43] Benediktsdottir, B.E., Gudjonsson, T., Baldursson, O., Masson, M., N-alkylation of highly quaternized chitosan derivatives affects the paracellular permeation enhancement in bronchial epithelia in vitro. Eur. J. Pharm. Biopharm., 2013 (in press). http://dx.doi.org/10.1016/j.ejpb.2013.04.002.
44. [44] Vllasaliu, D., Exposito-Harris, R., Heras, A., Casettari, L., Garnett, M., Illum, L., Stolnik, S., Tight junction modulation by chitosan nanoparticles: comparison with chitosan solution. Int. J. Pharm. 400 (2010), 183–193.
45. [45] Jia, X., Chen, X., Xu, Y., Han, X., Xu, Z., Tracing transport of chitosan nanoparticles and molecules in Caco-2 cells by fluorescent labeling. Carbohydr. Polym. 78 (2009), 323–329.
46. [46] Schipper, N.G.M., Olsson, S., Hoogstraate, J.A., deBoer, A.G., Vårum, K.M., Artursson, P., Chitosans as absorption enhancers for poorly absorbable drugs 2: mechanism of absorption enhancement. Pharm. Res. 14 (1997), 923–929.
47. [47] Huang, M., Khor, E., Lim, L.-Y., Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of molecular weight and degree of deacetylation. Pharm. Res. 21 (2004), 344–353.
48. [48] Benediktsdottir, B.E., Sorensen, K.K., Thygesen, M.B., Jensen, K.J., Gudjonsson, T., Baldursson, O., Masson, M., Regioselective fluorescent labeling of N, N, N-trimethyl chitosan via oxime formation. Carbohydr. Polym. 90 (2012), 1273–1280.
49. [49] Canali, M.M., Pedrotti, L.P., Balsinde, J., Ibarra, C., Correa, S.G., Chitosan enhances transcellular permeability in human and rat intestine epithelium. Eur. J. Pharm. Biopharm. 80 (2012), 418–425.
50. [50] Vachon, P.H., Beaulieu, J.F., Transient mosaic patterns of morphological and functional-differentiation in the Caco-2 cell-line. Gastroenterology 103 (1992), 414–423.
51. [51] Walter, E., Kissel, T., Transepithelial transport and metabolism of thyrotropin-releasing-hormone (Trh) in monolayers of a human intestinal-cell line (Caco-2) — evidence for an active-transport component. Pharm. Res. 11 (1994), 1575–1580.
52. [52] Hsu, L.-W., Lee, P.-L., Chen, C.-T., Mi, F.-L., Juang, J.-H., Hwang, S.-M., Ho, Y.-C., Sung, H.-W., Elucidating the signaling mechanism of an epithelial tight-junction opening induced by chitosan. Biomaterials 33 (2012), 6254–6263.
53. [53] Yeh, T.-H., Hsu, L.-W., Tseng, M.T., Lee, P.-L., Sonjae, K., Ho, Y.-C., Sung, H.-W., Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening. Biomaterials 32 (2011), 6164–6173.
54. [54] Wilder, R.L., Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Ann. Rheum. Dis. 61 (2002), ii96–ii99.
55. [55] Vonlaufen, A., Wiedle, G., Borisch, B., Birrer, S., Luder, P., Imhof, B.A., Integrin [agr]v[bgr]3 expression in colon carcinoma correlates with survival. Mod. Pathol. 14 (2001), 1126–1132.
56. [56] Illum, L., Farraj, N.F., Davis, S.S., Chitosan as a novel nasal delivery system for peptide drugs. Pharm. Res. 11 (1994), 1186–1189.
57. [57] Volpe, D.A., Variability in Caco-2 and MDCK cell-based intestinal permeability assays. J. Pharm. Sci. 97 (2008), 712–725.
58. [58] Schipper, N.G.M., Vårum, K.M., Artursson, P., Chitosans as absorption enhancers for poorly absorbable drugs. 1: influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells. Pharm. Res. 13 (1996), 1686–1692.
59. [59] Smith, J.M., Dornish, M., Wood, E.J., Involvement of protein kinase C in chitosan glutamate-mediated tight junction disruption. Biomaterials 26 (2005), 3269–3276.
60. [60] Borchard, G., Luessen, H.L., deBoer, A.G., Verhoef, J.C., Lehr, C.M., Junginger, H.E., The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. 3. Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J. Control. Release 39 (1996), 131–138.
61. [61] Smith, J., Wood, E., Dornish, M., Effect of chitosan on epithelial cell tight junctions. Pharm. Res. 21 (2004), 43–49.
62. [62] Ranaldi, G., Marigliano, I., Vespignani, I., Perozzi, G., Sambuy, Y., The effect of chitosan and other polycations on tight junction permeability in the human intestinal Caco-2 cell line. J. Nutr. Biochem. 13 (2002), 157–167.
63. [63] Kotze, A.F., Luessen, H.L., de Boer, A.G., Verhoef, J.C., Junginger, H.E., Chitosan for enhanced intestinal permeability: prospects for derivatives soluble in neutral and basic environments. Eur. J. Pharm. Sci. 7 (1999), 145–151.
64. [64] Florea, B.I., Thanou, M., Junginger, H.E., Borchard, G., Enhancement of bronchial octreotide absorption by chitosan and N-trimethyl chitosan shows linear in vitro/in vivo correlation. J. Control. Release 110 (2006), 353–361.
65. [65] Kotze, A.F., Luessen, H.L., de Leeuw, B.J., de Boer, B.G., Verhoef, J.C., Junginger, H.E., Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J. Control. Release 51 (1998), 35–46.
66. [66] Tezel, A., Mitragotri, S., On the origin of size-dependent tortuosity for permeation of hydrophilic solutes across the stratum corneum. J. Control. Release 86 (2003), 183–186.
67. [67] Kushner, J., Blankschtein, D., Langer, R., Evaluation of the porosity, the tortuosity, and the hindrance factor for the transdermal delivery of hydrophilic permeants in the context of the aqueous pore pathway hypothesis using dual-radiolabeled permeability experiments. J. Pharm. Sci. 96 (2007), 3263–3282.
68. [68] Dodane, V., Amin Khan, M., Merwin, J.R., Effect of chitosan on epithelial permeability and structure. Int. J. Pharm. 182 (1999), 21–32.
69. [69] Schipper, N.G.M., Varum, K.M., Stenberg, P., Ocklind, G., Lennernas, H., Artursson, P., Chitosans as absorption enhancers of poorly absorbable drugs 3: influence of mucus on absorption enhancement. Eur. J. Pharm. Sci. 8 (1999), 335–343.
70. [70] Rosenthal, R., Günzel, D., Finger, C., Krug, S.M., Richter, J.F., Schulzke, J.-D., Fromm, M., Amasheh, S., The effect of chitosan on transcellular and paracellular mechanisms in the intestinal epithelial barrier. Biomaterials 33 (2012), 2791–2800.
71. [71] Luessen, H.L., Rentel, C.O., Kotze, A.F., Lehr, C.M., deBoer, A.G., Verhoef, J.C., Junginger, H.E., Mucoadhesive polymers in peroral peptide drug delivery.4. Polycarbophil and chitosan are potent enhancers of peptide transport across intestinal mucosae in vitro. J. Control. Release 45 (1997), 15–23.
72. [72] Walters, D.V., Lung lining liquid — the hidden depths. Neonatology 81 (2002), 2–5.
73. [73] Scherließ, R., The MTT assay as tool to evaluate and compare excipient toxicity in vitro on respiratory epithelial cells. Int. J. Pharm. 411 (2011), 98–105.
74. [74] Jayaraman, S., Song, Y., Verkman, A.S., Airway surface liquid pH in well-differentiated airway epithelial cell cultures and mouse trachea. Am. J. Physiol. Cell Physiol. 281 (2001), C1504–C1511.
75. [75] Thanou, M., Florea, B.I., Langemeyer, M.W.E., Verhoef, J.C., Junginger, H.E., N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats). Pharm. Res. 17 (2000), 27–31.
76. [76] Hinchcliffe, M., Jabbal-Gill, I., Smith, A., Effect of chitosan on the intranasal absorption of salmon calcitonin in sheep. J. Pharm. Pharmacol. 57 (2005), 681–687.
77. [77] Luessen, H.L., deLeeuw, B.J., Langemeyer, M.W.E., deBoer, A.G., Verhoef, J.C., Junginger, H.E., Mucoadhesive polymers in peroral peptide drug delivery.6. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo. Pharm. Res. 13 (1996), 1668–1672.
78. [78] Mei, D., Mao, S.R., Sun, W., Wang, Y.J., Kissel, T., Effect of chitosan structure properties and molecular weight on the intranasal absorption of tetramethylpyrazine phosphate in rats. Eur. J. Pharm. Biopharm. 70 (2008), 874–881.
79. [79] Yu, S.Y., Zhao, Y., Wu, F.L., Zhang, X., Lu, W.L., Zhang, H., Zhang, Q., Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies. Int. J. Pharm. 281 (2004), 11–23.
80. [80] Gao, Y., He, L., Katsumi, H., Sakane, T., Fujita, T., Yamamoto, A., Improvement of intestinal absorption of insulin and water-soluble macromolecular compounds by chitosan oligomers in rats. Int. J. Pharm. 359 (2008), 70–78.
81. [81] Chen, W., Fan, D., Meng, L., Miao, Y., Yang, S., Weng, Y., He, H., Tang, X., Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats. Drug Dev. Ind. Pharm. 38 (2012), 104–110.
82. [82] Kowapradit, J., Opanasopit, P., Ngawhirunpat, T., Rojanarata, T., Sajomsang, W., Structure–activity relationships of methylated N-aryl chitosan derivatives for enhancing paracellular permeability across Caco-2 cells. Carbohydr. Polym. 83 (2011), 430–437.
83. [83] Thanou, M., Nihot, M.T., Jansen, M., Verhoef, J.C., Junginger, H.E., Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 90 (2001), 38–46.
84. [84] Zambito, Y., Fogli, S., Zaino, C., Stefanelli, F., Breschi, M.C., Di Colo, G., Synthesis, characterization and evaluation of thiolated quaternary ammonium–chitosan conjugates for enhanced intestinal drug permeation. Eur. J. Pharm. Sci. 38 (2009), 112–120.
85. [85] Polnok, A., Borchard, G., Verhoef, J.C., Sarisuta, N., Junginger, H.E., Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride. Eur. J. Pharm. Biopharm. 57 (2004), 77–83.
86. [86] Kumirska, J., Czerwicka, M., Kaczynski, Z., Bychowska, A., Brzozowski, K., Thoming, J., Stepnowski, P., Application of spectroscopic methods for structural analysis of chitin and chitosan. Mar. Drugs 8 (2010), 1567–1636.
87. [87] Runarsson, O.V., Holappa, J., Jonsdottir, S., Steinsson, H., Masson, M., N-selective ‘one pot’ synthesis of highly N-substituted trimethyl chitosan (TMC). Carbohydr. Polym. 74 (2008), 740–744.
88. [88] Holappa, J., Nevalainen, T., Soininen, P., Elomaa, M., Safin, R., Másson, M., Järvinen, T., N-Chloroacyl-6-O-triphenylmethylchitosans: Useful intermediates for synthetic modifications of chitosan. Biomacromolecules 6 (2005), 858–863.
89. [89] Sajomsang, W., Tantayanon, S., Tangpasuthadol, V., Daly, W.H., Quaternization of N-aryl chitosan derivatives: synthesis, characterization, and antibacterial activity. Carbohydr. Res. 344 (2009), 2502–2511.
90. [90] Benediktsdottir, B.E., Gaware, V.S., Runarsson, O.V., Jonsdottir, S., Jensen, K.J., Masson, M., Synthesis of N, N, N-trimethyl chitosan homopolymer and highly substituted N-alkyl-N, N-dimethyl chitosan derivatives with the aid of di-tert-butyldimethylsilyl chitosan. Carbohydr. Polym. 86 (2011), 1451–1460.
91. [91] Muzzarelli, R.A.A., Tanfani, F., The N-permethylation of chitosan and the preparation of N-trimethyl chitosan iodide. Carbohydr. Polym. 5 (1985), 297–307.
92. [92] Kim, C.H., Choi, J.W., Chun, H.J., Choi, K.S., Synthesis of chitosan derivatives with quaternary ammonium salt and their antibacterial activity. Polym. Bull. 38 (1997), 387–393.
93. [93] Jia, Z., shen, D., Xu, W., Synthesis and antibacterial activities of quaternary ammonium salt of chitosan. Carbohydr. Res. 333 (2001), 1–6.
94. [94] Verheul, R.J., Amidi, M., van der Wal, S., van Riet, E., Jiskoot, W., Hennink, W.E., Synthesis, characterization and in vitro biological properties of O-methyl free N, N, N-trimethylated chitosan. Biomaterials 29 (2008), 3642–3649.
95. [95] Ledung, P., Milas, M., Rinaudo, M., Desbrieres, J., Water-soluble derivatives obtained by controlled chemical modifications of chitosan. Carbohydr. Polym. 24 (1994), 209–214.
96. [96] Sieval, A.B., Thanou, M., Kotze, A.F., Verhoef, J.E., Brussee, J., Junginger, H.E., Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride. Carbohydr. Polym. 36 (1998), 157–165.
97. [97] Snyman, D., Hamman, J.H., Kotze, J.S., Rollings, J.E., Kotze, A.F., The relationship between the absolute molecular weight and the degree of quaternisation of N-trimethyl chitosan chloride. Carbohydr. Polym. 50 (2002), 145–150.
98. [98] de Britto, D., Assis, O.B.G., A novel method for obtaining a quaternary salt of chitosan. Carbohydr. Polym. 69 (2007), 305–310.
99. [99] Domard, A., Rinaudo, M., Terrassin, C., New method for the quaternization of chitosan. Int. J. Biol. Macromol. 8 (1986), 105–107.
100. [100] Holappa, J., Nevalainen, T., Savolainen, J., Soininen, P., Elomaa, M., Safin, R., Suvanto, S., Pakkanen, T., Masson, M., Loftsson, T., Jarvinen, T., Synthesis and characterization of chitosan N-betainates having various degrees of substitution. Macromolecules 37 (2004), 2784–2789.
101. [101] Kurita, K., Ikeda, H., Yoshida, Y., Shimojoh, M., Harata, M., Chemoselective protection of the amino groups of chitosan by controlled phthaloylation: facile preparation of a precursor useful for chemical modifications. Biomacromolecules 3 (2001), 1–4.
102. [102] Nishimura, S., Kohgo, O., Kurita, K., Kuzuhara, H., Chemospecific manipulations of a rigid polysaccharide: syntheses of novel chitosan derivatives with excellent solubility in common organic solvents by regioselective chemical modifications. Macromolecules 24 (1991), 4745–4748.
103. [103] Holappa, J., Nevalainen, T., Safin, R., Soininen, P., Asplund, T., Luttikhedde, T., Masson, M., Jarvinen, T., Novel water-soluble quaternary piperazine derivatives of chitosan: synthesis and characterization. Macromol. Biosci. 6 (2006), 139–144.
104. [104] Holappa, J., Nevalainen, T., Soininen, P., Elomaa, M., Safin, R., Masson, M., Jarvinen, T., N-chloroacyl-6-O-triphenylmethylchitosans: useful intermediates for synthetic modifications of chitosan. Biomacromolecules 6 (2005), 858–863.
105. [105] Runarsson, O.V., Holappa, J., Nevalainen, T., Hjalmarsdottir, M., Jarvinen, T., Loftsson, T., Einarsson, J.M., Jonsdottir, S., Valdimarsdottir, M., Masson, M., Antibacterial activity of methylated chitosan and chitooligomer derivatives: synthesis and structure activity relationships. Eur. Polym. J. 43 (2007), 2660–2671.
106. [106] Kurita, K., Hirakawa, M., Kikuchi, S., Yamanaka, H., Yang, J., Trimethylsilylation of chitosan and some properties of the product. Carbohydr. Polym. 56 (2004), 333–337.
107. [107] Wuts, P.G.W., Greene, T.W., Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols, in: Greene's Protective Groups in Organic Synthesis. 2007, John Wiley & Sons, Inc., New Jersey, 189–198.
108. [108] Runarsson, O.V., Malainer, C., Holappa, J., Sigurdsson, S.T., Masson, M., tert-Butyldimethylsilyl O-protected chitosan and chitooligosaccharides: useful precursors for N-modifications in common organic solvents. Carbohydr. Res. 343 (2008), 2576–2582.
109. [109] Song, W.L., Gaware, V.S., Runarsson, O.V., Masson, M., Mano, J.F., Functionalized superhydrophobic biomimetic chitosan-based films. Carbohydr. Polym. 81 (2010), 140–144.
110. [110] Binette, A., Gagnon, J., Regioselective silylation of N-phthaloylchitosan with TBDMS and TBDPS groups. Biomacromolecules 8 (2007), 1812–1815.
111. [111] Sandri, G., Bonferoni, M.C., Rossi, S., Ferrari, F., Boselli, C., Caramella, C., Insulin-loaded nanoparticles based on N-trimethyl chitosan: in vitro (Caco-2 model) and ex vivo (excised rat jejunum, duodenum, and ileum) evaluation of penetration enhancement properties. AAPS PharmSciTech 11 (2010), 362–371.
112. [112] Amidi, M., Romeijn, S.G., Borchard, G., Junginger, H.E., Hennink, W.E., Jiskoot, W., Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J. Control. Release 111 (2006), 107–116.
113. [113] Thanou, M.M., Kotze, A.F., Scharringhausen, T., Luessen, H.L., de Boer, A.G., Verhoef, J.C., Junginger, H.E., Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers. J. Control. Release 64 (2000), 15–25.
114. [114] Kotze, A.F., de Leeuw, B.J., Luessen, H.L., de Boer, A.G., Verhoef, J.C., Junginger, H.E., Chitosans for enhanced delivery of therapeutic peptides across intestinal epithelia: in vitro evaluation in Caco-2 cell monolayers. Int. J. Pharm. 159 (1997), 243–253.
115. [115] Dorkoosh, F.A., Broekhuizen, C.A.N., Borchard, G., Rafiee-Tehrani, M., Verhoef, J.C., Junginger, H.E., Transport of octreotide and evaluation of mechanism of opening the paracellular tight junctions using superporous hydrogel polymers in Caco-2 cell monolayers. J. Pharm. Sci. 93 (2004), 743–752.
116. [116] Kotze, A.F., Luessen, H.L., deLeeuw, B.J., deBoer, B.G., Verhoef, J.C., Junginger, H.E., N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces: in vitro evaluation in intestinal epithelial cells (Caco-2). Pharm. Res. 14 (1997), 1197–1202.
117. [117] Kotze, A.F., Thanou, M.M., Luessen, H.L., de Boer, B.G., Verhoef, J.C., Junginger, H.E., Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). Eur. J. Pharm. Biopharm. 47 (1999), 269–274.
118. [118] Kotze, A.F., Thanou, M.M., Luebetaen, H.L., de Boer, A.G., Verhoef, J.C., Junginger, H.E., Enhancement of paracellular drug transport with highly quaternized N-trimethyl chitosan chloride in neutral environments: in vitro evaluation in intestinal epithelial cells (Caco-2). J. Pharm. Sci. 88 (1999), 253–257.
119. [119] Jonker, C., Hamman, J.H., Kotze, A.F., Intestinal paracellular permeation enhancement with quaternised chitosan: in situ and in vitro evaluation. Int. J. Pharm. 238 (2002), 205–213.
120. [120] Thanou, M., Verhoef, J.C., Verheijden, J.H.M., Junginger, H.E., Intestinal absorption of octreotide using trimethyl chitosan chloride: studies in pigs. Pharm. Res. 18 (2001), 823–828.
121. [121] Hamman, J.H., Stander, M., Kotze, A.F., Effect of the degree of quaternisation of N-trimethyl chitosan chloride on absorption enhancement: in vivo evaluation in rat nasal epithelia. Int. J. Pharm. 232 (2002), 235–242.
122. [122] Strand, S.P., Tømmeraas, K., Vårum, K.M., Østgaard, K., Electrophoretic light scattering studies of chitosans with different degrees of N-acetylation. Biomacromolecules 2 (2001), 1310–1314.
123. [123] Opanasopit, P., Aumklad, P., Kowapradit, J., Ngawhiranpat, T., Apirakaramwong, A., Rojanarata, T., Effect of salt forms and molecular weight of chitosans on in vitro permeability enhancement in intestinal epithelial cells (Caco-2). Pharm. Dev. Technol. 12 (2007), 447–455.
124. [124] Sahni, J.K., Chopra, S., Ahmad, F.J., Khar, R.K., Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applications. J. Pharm. Pharmacol. 60 (2008), 1111–1119.
125. [125] Sonaje, K., Chuang, E.Y., Lin, K.J., Yen, T.C., Su, F.Y., Tseng, M.T., Sung, H.W., Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations. Mol. Pharm. 9 (2012), 1271–1279.
126. [126] Madara, J.L., Intestinal absorptive cell tight junctions are linked to cytoskeleton. Am. J. Physiol. Cell Physiol. 253 (1987), C171–C175.
127. [127] Frisch, S., Francis, H., Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124 (1994), 619–626.