Recently, increasing attention has been paid to water-soluble derivatives of chitosan at its applications. The chemical characteristics and the antimicrobial properties of these salts can play significant role in pharmacological and food areas mainly as carriers for drug delivery systems and as antimicrobial packaging materials. In the current paper, a historical sequence of the main preparative methods, physical chemistry aspects, and antimicrobial activity of chitosan quaternized derivatives are presented and briefly discussed. In general, the results indicated that the quaternary derivatives had better inhibitory effects than the unmodified chitosan. 1. Background One of the first reports about methylation process of chitosan was presented by Wolfrom et al. in their study on carboxyl-reduced heparin published in 1963 [1]. Despite employing a very methylant agent (dimethylsulfate), only a 3,6-O-methylated product was claimed by the authors. In the seventies, Nudga et al. studied a series of N-alkylated chitosans [2–4] and described the preparation of a derivative with a 78% of quaternary amino sites. Then, Muzzarelli and Tanfani, in 1985 [5], prepared N-trimethyl chitosan iodide in a controlled three-step reaction: (a) started by a preparation of an N-alkyl chitosan via reductive alkylation, in which the chitosan amino groups react with appropriated aldehyde, generating a Schiff’s base; (b) this compound is treated with a reducing agent, to yield the corresponding N-alkyl chitosan (c) then an overmethylation with an alkyl halide is carried out, generating, finally, the quaternary salt. With these sequences Muzzarelli and Tanfani obtained N,N,N-trimethyl chitosan (TMC) by reacting N-permethylated chitosan, which was previously prepared by treating chitosan with formaldehyde followed by reduction with sodium borohydrade and trimethylation with methyl iodide. Although, according to the authors, the product 60% trimethylated was not water soluble and characterized only with 13C NMR and elemental analysis. This effort was made, aiming its application as antibiotic and ion exchange material. In the following year, Domard et al. [6], also reacting chitosan with methyl iodide, gave an important contribution mainly on the role of the reagents in the quaternization. They established that the combination of N-methyl-2-pyrrolidone (NMP) and NaOH favors the quaternization better than sole addition of organic bases, for example, triethylamine. In order to understand the chemical structure of the TMC, several papers were published, emphasizing the features and
References
[1]
M. L. Wolfrom, J. R. Vercellotti, and D. Horton, “Methylation studies on carboxyl-reduced heparin- 2-amino-2-deoxy-3,6-di-O-methyl-alpha-d-glucopyranose from the methylation of chitosan,” Journal of Organic Chemistry, vol. 29, no. 3, pp. 547–550, 1964.
[2]
L. A. Nudga, E. A. Plisko, and S. N. Danilov, “Cyanoethylation of chitosan,” Zhurnal Obshchei Khimii, vol. 45, no. 5, pp. 1145–1149, 1975.
[3]
L. A. Nudga, E. A. Plisko, and S. N. Danilov, “O-alkylation of chitosan,” Zhurnal Obshchei Khimii, vol. 43, no. 12, pp. 2752–2756, 1973.
[4]
L. A. Nudga, E. A. Plisko, and S. N. Danilov, “N-alkylation of chitosan,” Zhurnal Obshchei Khimii, vol. 43, no. 12, pp. 2756–2760, 1973.
[5]
R. A. A. Muzzarelli and F. Tanfani, “The N-permethylation of chitosan and the preparation of N-trimethyl chitosan iodide,” Carbohydrate Polymers, vol. 5, no. 4, pp. 297–307, 1985.
[6]
A. Domard, M. Rinaudo, and C. Terrassin, “New method for the quaternization of chitosan,” International Journal of Biological Macromolecules, vol. 8, no. 2, pp. 105–107, 1986.
[7]
A. Domard, C. Gey, M. Rinaudo, and C. Terrassin, “13C and 1H n.m.r. spectroscopy of chitosan and N-trimethyl chloride derivatives,” International Journal of Biological Macromolecules, vol. 9, no. 4, pp. 233–237, 1987.
[8]
P. Dung, M. Milas, M. Rinaudo, and J. Desbrières, “Water soluble derivatives obtained by controlled chemical modifications of chitosan,” Carbohydrate Polymers, vol. 24, no. 3, pp. 209–214, 1994.
[9]
J. Murata, Y. Ohya, and T. Ouchi, “Possibility of application of quaternary chitosan having pendant galactose residues as gene delivery tool,” Carbohydrate Polymers, vol. 29, no. 1, pp. 69–74, 1996.
[10]
J. Murata, Y. Ohya, and T. Ouchi, “Design of quaternary chitosan conjugate having antennary galactose residues as a gene delivery tool,” Carbohydrate Polymers, vol. 32, no. 2, pp. 105–109, 1997.
[11]
T. Kean, S. Roth, and M. Thanou, “Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency,” Journal of Controlled Release, vol. 103, no. 3, pp. 643–653, 2005.
[12]
S. R. Mao, U. Bakowsky, A. Jintapattanakit, and T. Kissel, “Self-assembled polyelectrolyte nanocomplexes between chitosan derivatives and insulin,” Journal of Pharmaceutical Sciences, vol. 95, no. 5, pp. 1035–1048, 2006.
[13]
Z. W. Mao, L. Ma, Y. Jiang, M. Yan, C. Y. Gao, and J. C. Shen, “N,N,N-trimethylchitosan chloride as a gene vector: synthesis and application,” Macromolecular Bioscience, vol. 7, no. 6, pp. 855–863, 2007.
[14]
O. Germershaus, S. R. Mao, J. Sitterberg, U. Bakowsky, and T. Kissel, “Gene delivery using chitosan, trimethyl chitosan or polyethylenglycol-graft-trimethyl chitosan block copolymers: establishment of structure-activity relationships in vitro,” Journal of Controlled Release, vol. 125, no. 2, pp. 145–154, 2008.
[15]
W. Sajomsang, U. Ruktanonchai, P. Gonil, V. Mayen, and P. Opanasopit, “Methylated N-aryl chitosan derivative/DNA complex nanoparticles for gene delivery: synthesis and structure-activity relationships,” Carbohydrate Polymers, vol. 78, no. 4, pp. 743–752, 2009.
[16]
M. Werle, H. Takeuchi, and A. Bernkop-Schnurch, “Modified chitosans for oral drug delivery,” Journal of Pharmaceutical Sciences, vol. 98, no. 5, pp. 1643–1656, 2009.
[17]
M. N. V. R. Kumar, “A review of chitin and chitosan applications,” Reactive & Functional Polymers, vol. 46, no. 1, pp. 1–27, 2000.
[18]
I. Aranaz, M. Mengíbar, R. Harris et al., “Functional characterization of chitin and chitosan,” Current Chemical Biology, vol. 3, no. 2, pp. 203–230, 2009.
[19]
A. F. Kotze, H. L. Lue？en, B. J. de Leeuw, B. G. de Boer, J. C. Verhoef, and H. E. Junginger, “N-Trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces: in vitro evaluation in intestinal epithelial cells (Caco-2),” Pharmaceutical Research, vol. 14, no. 9, pp. 1197–1202, 1997.
[20]
A. F. Kotze, H. L. Lue？en, B. J. de Leeuw, B. G. de Boer, J. C. Verhoef, and H. E. Junginger, “Chitosans for enhanced delivery of therapeutic peptides across intestinal epithelia: in vitro evaluation in Caco-2 cell monolayers,” International Journal of Biological Macromolecules, vol. 159, no. 2, pp. 243–253, 1997.
[21]
A. F. Kotze, H. L. Lue？en, B. J. de Leeuw, B. G. de Boer, J. C. Verhoef, and H. E. Junginger, “Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2),” Journal of Controlled Release, vol. 51, no. 1, pp. 35–46, 1998.
[22]
A. B. Sieval, M. Thanou, A. F. Kotze, J. C. Verhoef, J. Brussee, and H. E. Junginger, “Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride,” Carbohydrate Polymers, vol. 36, no. 2-3, pp. 157–165, 1998.
[23]
A. F. Kotze, M. M. Thanou, H. L. Lue？en, B. G. de Boer, J. C. Verhoef, and H. E. Junginger, “Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2),” European Journal of Pharmaceutics and Biopharmaceutics, vol. 47, no. 3, pp. 269–274, 1999.
[24]
M. M. Thanou, A. F. Kotze, T. Scharringhausen et al., “Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers,” Journal of Controlled Release, vol. 64, no. 1–3, pp. 15–25, 2000.
[25]
J. H. Hamman and A. F. Kotze, “Effect of the type of base and number of reaction steps on the degree of quaternization and molecular weight of N-trimethyl chitosan chloride,” Drug Development and Industrial Pharmacy, vol. 27, no. 5, pp. 373–380, 2001.
[26]
J. H. Hamman, M. Stander, and A. F. Kotze, “Effect of the degree of quaternisation of N-trimethyl chitosan chloride on absorption enhancement: in vivo evaluation in rat nasal epithelia,” International Journal of Pharmaceutics, vol. 232, no. 1-2, pp. 235–242, 2002.
[27]
D. Snyman, J. H. Hamman, J. S. Kotze, J. E. Rollings, and A. F. Kotze, “The relationship between the absolute molecular weight and the degree of quaternisation of N-trimethyl chitosan chloride,” Carbohydrate Polymers, vol. 50, no. 2, pp. 145–150, 2002.
[28]
S. M. van der Merwe, J. C. Verhoef, J. H. M. Verheijden, A. F. Kotze, and H. E. Junginger, “Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 58, no. 2, pp. 225–235, 2004.
[29]
A. Polnok, G. Borchard, J. C. Verhoef, N. Sarisuta, and H. E. Junginger, “Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 57, no. 1, pp. 77–83, 2004.
[30]
C. Jonker-Venter, D. Snyman, C. J. Van Rensburg et al., “Low molecular weight quaternised chitosan (II): in vitro assessment of absorption enhancing properties,” Pharmazie, vol. 61, no. 4, pp. 301–305, 2006.
[31]
G. Sandri, S. Rossi, M. C. Bonferoni et al., “Buccal penetration enhancement properties of N-trimethyl chitosan: influence of quaternization degree on absorption of a high molecular weight molecule,” International Journal of Pharmaceutics, vol. 297, no. 1-2, pp. 146–155, 2005.
[32]
G. Sandri, S. Rossi, M. C. Bonferoni et al., “Influence of N-trimethylation degree on buccal penetration enhancement properties of N-trimethyl chitosan: absorption of a high molecular weight molecule,” European Journal of Pharmaceutical Sciences, vol. 25, supplement 1, pp. S8–S10, 2005.
[33]
B. I. Florea, M. Thanou, H. E. Junginger, and G. Borchard, “Enhancement of bronchial octreotide absorption by chitosan and N-trimethyl chitosan shows linear in vitro/in vivo correlation,” Journal of Controlled Release, vol. 110, no. 2, pp. 353–361, 2006.
[34]
Y. Zambito, C. Zaino, S. Burchielli, V. Carelli, M. F. Serafini, and G. Di Colo, “Novel quaternary ammonium chitosan derivatives for the promotion of intraocular drug absorption,” Journal of Drug Delivery Science and Technology, vol. 17, no. 1, pp. 19–24, 2007.
[35]
W. He, X. X. Guo, and M. Zhang, “Transdermal permeation enhancement of N-trimethyl chitosan for testosterone,” International Journal of Pharmaceutics, vol. 356, no. 1-2, pp. 82–87, 2008.
[36]
M. C. Bonferoni, G. Sandri, S. Rossi, F. Ferrari, and C. Caramella, “Chitosan and its salts for mucosal and transmucosal delivery,” Expert Opinion on Drug Delivery, vol. 6, no. 9, pp. 923–939, 2009.
[37]
V. K. Mourya and N. N. Inamdar, “Trimethyl chitosan and its applications in drug delivery,” Journal of Materials Science, vol. 20, no. 5, pp. 1057–1079, 2009.
[38]
J. K. Sahni, S. Chopra, F. J. Ahmad, and R. K. Khar, “Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applications,” Journal of Pharmacy and Pharmacology, vol. 60, no. 9, pp. 1111–1119, 2008.
[39]
G. Lang, H. Wendel, and S. Birkel, “Quaternary chitosan salts,” in Chitin Handbook, R. A. A. Muzzarelli and M. G. Peter, Eds., pp. 384–389, European Chitin Society press, Grottammare, Italy, 1997.
[40]
C. H. Kim, J. W. Choi, H. J. Chun, and K. S. Choi, “Synthesis of chitosan derivatives with quaternary ammonium salt and their antibacterial activity,” Polymer Bulletin, vol. 38, no. 4, pp. 387–393, 1997.
[41]
Z. Jia, D. Shen, and W. Xu, “Synthesis and antibacterial activities of quaternary ammonium salt of chitosan,” Carbohydrate Research, vol. 333, no. 1, pp. 1–6, 2001.
[42]
W. Sajomsang, S. Tantayanon, V. Tangpasuthadol, and W. H. Daly, “Synthesis of methylated chitosan containing aromatic moieties: chemoselectivity and effect on molecular weight,” Carbohydrate Polymers, vol. 72, no. 4, pp. 740–750, 2008.
[43]
W. Sajomsang, P. Gonil, and S. Saesoo, “Synthesis and antibacterial activity of methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride,” European Polymer Journal, vol. 45, no. 8, pp. 2319–2328, 2009.
[44]
T. Xu, M. Xin, M. Li, H. Huang, and S. Zhou, “Synthesis, characteristic and antibacterial activity of N,N,N-trimethyl chitosan and its carboxymethyl derivatives,” Carbohydrate Polymers, vol. 81, no. 4, pp. 931–936, 2010.
[45]
？. V. Rúnarsson, J. Holappa, C. Malainer et al., “Antibacterial activity of N-quaternary chitosan derivatives: synthesis, characterization and structure activity relationship (SAR) investigations,” European Polymer Journal, vol. 46, no. 6, pp. 1251–1267, 2010.
[46]
E. Curti, D. de Britto, and S. P. Campana-Filho, “Methylation of chitosan with iodomethane: effect of reaction conditions on chemoselectivity and degree of substitution,” Macromolecular Bioscience, vol. 3, no. 10, pp. 571–576, 2003.
[47]
D. de Britto and S. P. Campana-Filho, “A kinetic study on the thermal degradation of N,N,N-trimethylchitosan,” Polymer Degradation and Stability, vol. 84, no. 2, pp. 353–361, 2004.
[48]
E. Curti and S. P. Campana-Filho, “Viscosity behavior of chitosan and N,N,N-trimethylchitosan chloride salts in acid-free aqueous solution,” Journal of Macromolecular Science, vol. 43, no. 3, pp. 555–572, 2006.
[49]
D. de Britto and O. B. G. Assis, “A novel method for obtaining a quaternary salt of chitosan,” Carbohydrate Polymers, vol. 69, no. 2, pp. 305–310, 2007.
[50]
D. de Britto and O. B. G. Assis, “Synthesis and mechanical properties of quaternary salts of chitosan-based films for food application,” International Journal of Biological Macromolecules, vol. 41, no. 2, pp. 198–203, 2007.
[51]
D. de Britto, L. A. Forato, and O. B. G. Assis, “Determination of the average degree of quaternization of N,N,N-trimethylchitosan by solid state 13C NMR,” Carbohydrate Polymers, vol. 74, no. 1, pp. 86–91, 2008.
[52]
R. J. Verheul, M. Amidi, S. van der Wal, E. van Riet, W. Jiskoot, and W. E. Hennink, “Synthesis, characterization and in vitro biological properties of O-methyl free N,N,N-trimethylated chitosan,” Biomaterials, vol. 29, no. 27, pp. 3642–3649, 2008.
[53]
O. V. Rúnarsson, J. Holappa, S. Jónsdóttir, H. Steinsson, and M. Másson, “N-selective ‘one pot’ synthesis of highly N-substituted trimethyl chitosan (TMC),” Carbohydrate Polymers, vol. 74, no. 3, pp. 740–744, 2008.
[54]
Y. M. Xu, Y. M. Du, R. H. Huang, and L. Gao, “Preparation and modification of N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride nanoparticle as a protein carrier,” Biomaterials, vol. 24, no. 27, pp. 5015–5022, 2003.
[55]
M. Amidi, S. G. Romeijn, G. Borchard, H. E. Junginger, W. E. Hennink, and W. Jiskoot, “Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system,” Journal of Controlled Release, vol. 111, no. 1-2, pp. 107–116, 2006.
[56]
M. Amidi, S. G. Romeijn, J. C. Verhoef et al., “N-Trimethyl chitosan (TMC) nanoparticles loaded with influenza subunit antigen for intranasal vaccination: biological properties and immunogenicity in a mouse model,” Vaccine, vol. 25, no. 1, pp. 144–153, 2007.
[57]
B. Sayin, S. Somavarapu, X. W. Li et al., “Mono-N-carboxymethyl chitosan (MCC) and N-trimethyl chitosan (TMC) nanoparticles for non-invasive vaccine delivery,” International Journal of Pharmaceutics, vol. 363, no. 1-2, pp. 139–148, 2008.
[58]
B. Slutter, L. Plapied, V. Fievez et al., “Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination,” Journal of Controlled Release, vol. 138, no. 2, pp. 113–121, 2009.
[59]
F. Chen, Z. R. Zhang, and Y. Huang, “Evaluation and modification of N-trimethyl chitosan chloride nanoparticles as protein carriers,” International Journal of Pharmaceutics, vol. 336, no. 1, pp. 166–173, 2007.
[60]
Y. Sun and A. J. Wan, “Preparation of nanoparticles composed of chitosan and its derivatives as delivery systems for macromolecules,” Journal of Applied Polymer Science, vol. 105, no. 2, pp. 552–561, 2007.
[61]
F. Chen, Z. R. Zhang, F. Yuan, X. Qin, M. T. Wang, and Y. Huang, “In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery,” International Journal of Pharmaceutics, vol. 349, no. 1-2, pp. 226–233, 2008.
[62]
A. M. M. Sadeghi, F. A. Dorkoosh, M. R. Avadi, P. Saadat, M. Rafiee-Tehrani, and H. E. Junginger, “Preparation, characterization and antibacterial activities of chitosan, N-trimethyl chitosan (TMC) and N-diethylmethyl chitosan (DEMC) nanoparticles loaded with insulin using both the ionotropic gelation and polyelectrolyte complexation methods,” International Journal of Pharmaceutics, vol. 355, no. 1-2, pp. 299–306, 2008.
[63]
J. Haas, M. N. V. R. Kumar, G. Borchard, U. Bakowsky, and C. M. Lehr, “Preparation and characterization of chitosan and trimethyl-chitosan modified poly-(ε-caprolactone) nanoparticles as DNA carriers,” AAPS PharmSciTech, vol. 6, no. 1, pp. E22–E30, 2005.
[64]
S. Mao, O. Germershaus, D. Fischer, T. Linn, R. Schnepf, and T. Kissel, “Uptake and transport of PEG-graft-trimethyl-chitosan copolymer-insulin nanocomplexes by epithelial cells,” Pharmaceutical Research, vol. 22, no. 12, pp. 2058–2068, 2005.
[65]
S. Mao, U. Bakowsky, A. Jintapattanakit, and T. Kissel, “Self-assembled polyelectrolyte nanocomplexes between chitosan derivatives and insulin,” Journal of Pharmaceutical Sciences, vol. 95, no. 5, pp. 1035–1048, 2006.
[66]
L. C. Yin, J. Y. Ding, C. B. He, L. M. Cui, C. Tang, and C. H. Yin, “Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery,” Biomaterials, vol. 30, no. 29, pp. 5691–5700, 2009.
[67]
Y. Ding, X. H. Xia, and C. Zhang, “Synthesis of metallic nanoparticles protected with N,N,N-trimethyl chitosan chloride via a relatively weak affinity,” Nanotechnology, vol. 17, no. 16, pp. 4156–4162, 2006.
[68]
X. J. Yuan, Z. R. Zhang, Q. G. Song, and Q. He, “Research on thymopentin loaded oral N-trimethyl chitosan nanoparticles,” Archives of Pharmacal Research, vol. 29, no. 9, pp. 795–799, 2006.
[69]
S. Cafaggi, E. Russo, R. Stefani et al., “Preparation and evaluation of nanoparticles made of chitosan or N-trimethyl chitosan and a cisplatin-alginate complex,” Journal of Controlled Release, vol. 121, no. 1-2, pp. 110–123, 2007.
[70]
Y. Zheng, Z. Cai, X. Song et al., “Preparation and characterization of folate conjugated N-trimethyl chitosan nanoparticles as protein carrier targeting folate receptor: in vitro studies,” Journal of Drug Targeting, vol. 17, no. 4, pp. 294–303, 2009.
[71]
C. Zhang, Y. Ding, Q. E. Ping, and L. L. Yu, “Novel chitosan-derived nanomaterials and their micelle-forming properties,” Journal of Agricultural and Food Chemistry, vol. 54, no. 22, pp. 8409–8416, 2006.
[72]
C. Zhang, Y. Ding, L. L. Yu, and Q. Ping, “Polymeric micelle systems of hydroxycamptothecin based on amphiphilic N-alkyl-N-trimethyl chitosan derivatives,” Colloids and Surfaces B, vol. 55, no. 2, pp. 192–199, 2007.
[73]
F. L. Mi, Y. Y. Wu, Y. H. Lin et al., “Oral delivery of peptide drugs using nanoparticles self-assembled by poly(γ-glutamic acid) and a chitosan derivative functionalized by trimethylation,” Bioconjugate Chemistry, vol. 19, no. 6, pp. 1248–1255, 2008.
[74]
A. M. M. Sadeghi, F. A. Dorkoosh, M. R. Avadi et al., “Permeation enhancer effect of chitosan and chitosan derivatives: comparison of formulations as soluble polymers and nanoparticulate systems on insulin absorption in Caco-2 cells,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 70, no. 1, pp. 270–278, 2008.
[75]
K. Van de Velde and P. Kiekens, “Structure analysis and degree of substitution of chitin, chitosan and dibutyrylchitin by FT-IR spectroscopy and solid state 13C NMR,” Carbohydrate Polymers, vol. 58, no. 4, pp. 409–416, 2004.
[76]
W. Boonyo, H. E. Junginger, N. Waranuch, A. Polnok, and T. Pitaksuteepong, “Chitosan and trimethyl chitosan chloride (TMC) as adjuvants for inducing immune responses to ovalbumin in mice following nasal administration,” Journal of Controlled Release, vol. 121, no. 3, pp. 168–175, 2007.
[77]
A. Jintapattanakit, S. Mao, T. Kissel, and V. B. Junyaprasert, “Physicochemical properties and biocompatibility of N-trimethyl chitosan: effect of quaternization and dimethylation,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 70, no. 2, pp. 563–571, 2008.
[78]
R. J. Verheul, M. Amidi, M. J. van Steenbergen, E. van Riet, W. Jiskoot, and W. E. Hennink, “Influence of the degree of acetylation on the enzymatic degradation and in vitro biological properties of trimethylated chitosans,” Biomaterials, vol. 30, no. 18, pp. 3129–3135, 2009.
[79]
N. Hagenaars, R. J. Verheul, I. Mooren et al., “Relationship between structure and adjuvanticity of N,N,N-trimethyl chitosan (TMC) structural variants in a nasal influenza vaccine,” Journal of Controlled Release, vol. 140, no. 2, pp. 126–133, 2009.
[80]
B. Slütter, P. C. Soema, Z. Ding, R. Verheul, W. Hennink, and W. Jiskoot, “Conjugation of ovalbumin to trimethyl chitosan improves immunogenicity of the antigen,” Journal of Controlled Release, vol. 143, no. 2, pp. 207–214, 2010.
[81]
P. Vongchan, Y. Wutti-In, W. Sajomsang, P. Gonil, S. Kothan, and R. J. Linhardt, “N,N,N-Trimethyl chitosan nanoparticles for the delivery of monoclonal antibodies against hepatocellular carcinoma cells,” Carbohydrate Polymers, vol. 85, no. 1, pp. 215–220, 2011.
[82]
D. de Britto, F. R. Frederico, and O. B. Garrido Assis, “Optimization of N, N, N-trimethylchitosan synthesis by factorial design,” Polymer International, vol. 60, no. 6, pp. 910–915, 2011.
[83]
D. de Britto, Estudos da obten？？o e das propriedades de carboximetilcelulose (CMC) e N,N,N-trimetilquitosana (TMQ) e das intera？？es do complexo polieletrolítico CMC/TMC com Cu2+, ácido húmico e atrazina, Ph.D. thesis, USP/IQSC, S？o Carlos, Brazil, 2003.
[84]
D. de Britto and O. B. G. Assis, “Hydrophilic and morphological aspects of films based on quaternary salts of chitosan for edible applications,” Packaging Technology and Science, vol. 23, no. 2, pp. 111–119, 2010.
[85]
R. C. Goy, D. de Britto, and O. B. G. Assis, “A Review of the Antimicrobial Activity of Chitosan,” Polímeros: Ciência e Tecnologia, vol. 19, no. 3, pp. 241–247, 2009.
[86]
M. Kong, X. G. Chen, K. Xing, and H. J. Park, “Antimicrobial properties of chitosan and mode of action: a state of the art review,” International Journal of Food Microbiology, vol. 144, no. 1, pp. 51–63, 2010.
[87]
E. I. Rabea, M. E. -T. Badawy, C. V. Stevens, G. Smagghe, and W. Steurbaut, “Chitosan as antimicrobial agent: applications and mode of action,” Biomacromolecules, vol. 4, no. 6, pp. 1457–1465, 2003.
[88]
？. V. Rúnarsson, J. Holappa, T. Nevalainen et al., “Antibacterial activity of methylated chitosan and chitooligomer derivatives: synthesis and structure activity relationships,” European Polymer Journal, vol. 43, no. 6, pp. 2660–2671, 2007.
[89]
M. R. Avadi, A. M. M. Sadeghi, A. Tahzibi et al., “Diethylmethyl chitosan as an antimicrobial agent: synthesis, characterization and antibacterial effects,” European Polymer Journal, vol. 40, no. 7, pp. 1355–1361, 2004.
[90]
W. Sajomsang, S. Tantayanon, V. Tangpasuthadol, and W. H. Daly, “Quaternization of N-aryl chitosan derivatives: synthesis, characterization, and antibacterial activity,” Carbohydrate Research, vol. 344, no. 18, pp. 2502–2511, 2009.
[91]
W. Sajomsang, P. Gonil, and S. Tantayanon, “Antibacterial activity of quaternary ammonium chitosan containing mono or disaccharide moieties: preparation and characterization,” International Journal of Biological Macromolecules, vol. 44, no. 5, pp. 419–427, 2009.
[92]
J. Y. Kim, J. K. Lee, T. S. Lee, and W. H. Park, “Synthesis of chitooligosaccharide derivative with quaternary ammonium group and its antimicrobial activity against Streptococcus mutans,” International Journal of Biological Macromolecules, vol. 32, no. 1-2, pp. 23–27, 2003.
[93]
R. Belalia, S. Grelier, M. Benaissa, and V. Coma, “New bioactive biomaterials based on quaternized chitosan,” Journal of Agricultural and Food Chemistry, vol. 56, no. 5, pp. 1582–1588, 2008.
[94]
M. Ignatova, K. Starbova, N. Markova, N. Manolova, and I. Rashkov, “Electrospun nano-fibre mats with antibacterial properties from quaternised chitosan and poly(vinyl alcohol),” Carbohydrate Research, vol. 341, no. 12, pp. 2098–2107, 2006.
[95]
M. Ignatova, N. Manolova, and I. Rashkov, “Novel antibacterial fibers of quaternized chitosan and poly(vinyl pyrrolidone) prepared by electrospinning,” European Polymer Journal, vol. 43, no. 4, pp. 1112–1122, 2007.
[96]
X. Fu, Y. Shen, X. Jiang, D. Huang, and Y. Yan, “Chitosan derivatives with dual-antibacterial functional groups for antimicrobial finishing of cotton fabrics,” Carbohydrate Polymers, vol. 85, no. 1, pp. 221–227, 2011.
[97]
R. C. Goy, D. de Britto, and O. B. G. Assis, “Antimicrobial analysis of gels and films from chitosan and N,N,N-trimethyl chitosan,” in Advances in Chitin Science, T. T. Franco and M. G. Peter, Eds., vol. 12, pp. 129–132, Unicamp/University of Potsdam, Potsdam, Germany, 2010.
[98]
F. Shahidi, J. K. V. Arachchi, and Y. -J. Jeon, “Food applications of chitin and chitosans,” Trends in Food Science and Technology, vol. 10, no. 2, pp. 37–51, 1999.
[99]
S. B. Ba？os, A. N. H. Lauzardo, M. G. V. del Valle et al., “Chitosan as a potential natural compound to control pre and postharvest diseases of horticultural commodities,” Crop Protection, vol. 25, no. 2, pp. 108–118, 2006.
[100]
H. K. No, S. P. Meyers, W. Prinyawiwatkul, and Z. Xu, “Applications of chitosan for improvement of quality and shelf life of foods: a review,” Journal of Food Science, vol. 72, no. 5, pp. R87–R100, 2007.
[101]
T. Yu, H. Y. Li, and X. D. Zheng, “Synergistic effect of chitosan and Cryptococcus laurentii on inhibition of Penicillium expansum infections,” International Journal of Food Microbiology, vol. 114, no. 3, pp. 261–266, 2007.
[102]
C. L. Wilson, A. El-Ghaouth, and M. E. Wisniewski, “Synergistic combinations of natural of compounds that control decay of fruits and vegetables and reduce contamination by food borne human pathogens,” Patent number US 20030113421 A1, 2003.
[103]
C. L. Wilson and A. El-Ghaouth, “Biological coating with a protective and curative effect for the control of postharvest decay,” Patent number US 6,423,310 B1, 2002.
[104]
A. El-Ghaouth, J. Arul, A. Asselin, and N. Benhamou, “Antifungal activity of chitosan on postharvest pathogens—induction of morphological and cytological alterations in Rhizopus-stolonifer,” Mycological Research, vol. 96, no. 9, pp. 769–779, 1992.
[105]
A. El-Ghaouth, J. L. Smilanick, and C. L. Wilson, “Enhancement of the performance of Candida saitoana by the addition of glycolchitosan for the control of postharvest decay of apple and citrus fruit,” Postharvest Biology and Technology, vol. 19, no. 1, pp. 103–110, 2000.
[106]
M. Eweis, S. S. Elkholy, and M. Z. Elsabee, “Antifungal efficacy of chitosan and its thiourea derivatives upon the growth of some sugar-beet pathogens,” International Journal of Biological Macromolecules, vol. 38, no. 1, pp. 1–8, 2006.
[107]
M. E. I. Badawy, E. I. Rabea, T. M. Rogge et al., “Synthesis and fungicidal activity of new N,O-acyl chitosan derivatives,” Biomacromolecules, vol. 5, no. 2, pp. 589–595, 2004.
[108]
E. I. Rabea, M. E. I. Badawy, T. M. Rogge et al., “Insecticidal and fungicidal activity of new synthesized chitosan derivatives,” Pest Management Science, vol. 61, no. 10, pp. 951–960, 2005.
[109]
E. I. Rabea, M. E. I. Badawy, T. M. Rogge et al., “Enhancement of fungicidal and insecticidal activity by reductive alkylation of chitosan,” Pest Management Science, vol. 62, no. 9, pp. 890–897, 2006.
[110]
E. I. Rabea, M. E. I. Badawy, W. Steurbaut, and C. V. Stevens, “In vitro assessment of N-(benzyl)chitosan derivatives against some plant pathogenic bacteria and fungi,” European Polymer Journal, vol. 45, no. 1, pp. 237–245, 2009.
[111]
M. E. I. Badawy, “Structure and antimicrobial activity relationship of quaternary N-alkyl chitosan derivatives against some plant pathogens,” Journal of Applied Polymer Science, vol. 117, no. 2, pp. 960–969, 2010.
[112]
R. Li, Z. Guo, and P. Jiang, “Synthesis, characterization, and antifungal activity of novel quaternary chitosan derivatives,” Carbohydrate Research, vol. 345, no. 13, pp. 1896–1900, 2010.
[113]
D. Britto, S. P. Campana Filho, and O. B. G. Assis, “Chitosan-based coatings for lightly processed food,” in Proceedings of the 10th International Conference on Chitin and Chitosan Advances in Chitin Science, A. Domard, E. Guibal, and K. M. V？rum, Eds., vol. 9, Montpellier, France, 2006.
