Chitosan-Based Nanoparticulate Systems: Implication Towards Therapeutics Application



Recently polymeric nanoparticulate systems have gained a great impetus in the biopharmaceutical research, primarily due to their ability to enhance the pharmacokinetics and pharmacodynamics of various drugs and bioactives. Some of these polymeric systems render an improved biodegradability and biocompatible properties. There is a wide array of natural and synthetic polymers that have been utilized to develop various nanocarriers for delivery of drugs, genes, and other bioactive compounds. Polymeric nanoparticles offer moderately high encapsulation efficiency, along with enhancement of stealth properties in the circulatory system when suitably surface modified, which further ensures a sustained release of the encapsulated agent. Moreover, the polymeric nanoparticles have a mesh-like framework that can accommodate bioactive materials along with a drug moiety forming a dual delivery system, which can be further coated with another polymer giving rise to core–shell nano-conjugate system to offer better targeting of drugs/genes and bioactives. Chitosan and their chitosan derivatives have found applications in various delivery systems. Chitosan is one of the abundant biopolymers existing in nature, which has made it a polymer of choice in various drug delivery applications. This chapter focuses on the practical considerations for development of chitosan nanoparticles, along with a detailed account of various genes and bioactives that may be encapsulated or loaded on to them. Further, emphasis will be given on the physicochemical behavior of such systems and their subsequent cellular responses, besides their biodistribution and toxicity profiles. The discussion will also highlight the implication of polymeric nanoparticles in various therapies and limitations pertaining to them. The manuscript will also address the commercial status of polymeric nanoparticles.


Chitosan Nanoparticles Drug delivery Gene delivery and protein delivery 


  1. Agnihotri SA, Aminabhavi TM (2004) Controlled release of clozapine through chitosan microparticles prepared by a novel method. J Control Release 96:245–259PubMedCrossRefGoogle Scholar
  2. Aiedeh K, Taha MO (2001) Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustained-release beads. Eur J Pharm Sci 13:159–168PubMedCrossRefGoogle Scholar
  3. Aiedeh K, Taha M, Al-Khatib H (2005) Evaluation of chitosan succinate and chitosan phthalate as enteric coating polymers for diclofenac sodium tablets. J Drug Deliv Sci Tec 15:207–211CrossRefGoogle Scholar
  4. Akbuǧa J, Durmaz G (1994) Preparation and evaluation of cross-linked chitosan microspheres containing furosemide. Int J Pharm 111:217–222CrossRefGoogle Scholar
  5. Alves N, Mano J (2008) Chitosan derivatives obtained by chemical modifications for biomedical and environmental applications. Int J Biol Macromol 43:401–414PubMedCrossRefGoogle Scholar
  6. Amidi M, Romeijn SG, Borchard G et al (2006) Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J Control Release 111:107–116PubMedCrossRefGoogle Scholar
  7. Amidi M, Pellikaan HC, Hirschberg H et al (2007a) Diphtheria toxoid-containing microparticulate powder formulations for pulmonary vaccination: preparation, characterization and evaluation in guinea pigs. Vaccine 25:6818–6829PubMedCrossRefGoogle Scholar
  8. Amidi M, Romeijn SG, Verhoef JC et al (2007b) N-trimethyl chitosan (TMC) nanoparticles loaded with influenza subunit antigen for intranasal vaccination: biological properties and immunogenicity in a mouse model. Vaccine 25:144–153PubMedCrossRefGoogle Scholar
  9. Amidi M, Krudys KM, Snel CJ et al (2008a) Efficacy of pulmonary insulin delivery in diabetic rats: use of a model-based approach in the evaluation of insulin powder formulations. J Control Release 127:257–266PubMedCrossRefGoogle Scholar
  10. Amidi M, Pellikaan HC, de Boer AH et al (2008b) Preparation and physicochemical characterization of supercritically dried insulin-loaded microparticles for pulmonary delivery. Eur J Pharm Biopharm 68:191–200PubMedCrossRefGoogle Scholar
  11. Andreas B, Hornof M, Zoidl T (2003) Thiolated polymers–thiomers: modification of chitosan with 2-iminothiolane. Int J Pharm 260:229–237CrossRefGoogle Scholar
  12. Anitha A, Rani VD, Krishna R et al (2009) Synthesis, characterization, cytotoxicity and antibacterial studies of chitosan, O-carboxymethyl and N, O-carboxymethyl chitosan nanoparticles. Carbohyd Polym 78:672–677CrossRefGoogle Scholar
  13. Anitha A, Deepa N, Chennazhi K et al (2011) Development of mucoadhesive thiolated chitosan nanoparticles for biomedical applications. Carbohyd Polym 83:66–73CrossRefGoogle Scholar
  14. Aranaz I, Harris R, Heras A (2010) Chitosan amphiphilic derivatives. Chemistry and applications. Curr Org Chem 14:308CrossRefGoogle Scholar
  15. Artursson P, Lindmark T, Davis SS et al (1994) Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharmaceut Res 11:1358–1361CrossRefGoogle Scholar
  16. Aydin Z, Akbuǧa J (1996) Chitosan beads for the delivery of salmon calcitonin: preparation and release characteristics. Int J Pharm 131:101–103CrossRefGoogle Scholar
  17. Bachar G, Cohen K, Hod R et al (2011) Hyaluronan-grafted particle clusters loaded with Mitomycin C as selective nanovectors for primary head and neck cancers. Biomaterials 32:4840–4848PubMedCrossRefGoogle Scholar
  18. Banerjee T, Mitra S, Singh AK et al (2002) Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles. Int J Pharm 243:93–105PubMedCrossRefGoogle Scholar
  19. Banerjee T, Singh A, Sharma R et al (2005) Labeling efficiency and biodistribution of Technetium-99m labeled nanoparticles: interference by colloidal tin oxide particles. Int J Pharm 289:189–195PubMedCrossRefGoogle Scholar
  20. Bayat A, Dorkoosh FA, Dehpour AR et al (2008) Nanoparticles of quaternized chitosan derivatives as a carrier for colon delivery of insulin: ex vivo and in vivo studies. Int J Pharm 356:259–266PubMedCrossRefGoogle Scholar
  21. Bernkop-Schnürch A, Dünnhaupt S (2012) Chitosan-based drug delivery systems. Eur J Pharm Biopharm 81:463–469PubMedCrossRefGoogle Scholar
  22. Berscht PC, Nies B, Liebendörfer A et al (1994) Incorporation of basic fibroblast growth factor into methylpyrrolidinone chitosan fleeces and determination of the in vitro release characteristics. Biomaterials 15:593–600PubMedCrossRefGoogle Scholar
  23. Bhumkar DR, Joshi HM, Sastry M et al (2007) Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin. Pharmaceut Res 24:1415–1426CrossRefGoogle Scholar
  24. Bivas-Benita M, van Meijgaarden KE, Franken KL et al (2004) Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A* 0201-restricted T-cell epitopes of Mycobacterium tuberculosis. Vaccine 22:1609–1615PubMedCrossRefGoogle Scholar
  25. Bodmeier R, Oh K-H, Pramar Y (1989) Preparation and evaluation of drug-containing chitosan beads. Drug Dev Ind Pharm 15:1475–1494CrossRefGoogle Scholar
  26. Bodnar M, Hartmann JF, Borbely J (2005) Preparation and characterization of chitosan-based nanoparticles. Biomacromol 6:2521–2527CrossRefGoogle Scholar
  27. Bodnar M, Hartmann JF, Borbely J (2006) Synthesis and study of cross-linked chitosan-N-poly (ethylene glycol) nanoparticles. Biomacromol 7:3030–3036CrossRefGoogle Scholar
  28. Boonyo W, Junginger HE, Waranuch N et al (2007) Chitosan and trimethyl chitosan chloride (TMC) as adjuvants for inducing immune responses to ovalbumin in mice following nasal administration. J Control Release 121:168–175PubMedCrossRefGoogle Scholar
  29. Borchard G, Lueβen HL, de Boer AG et al (1996) The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release 39:131–138CrossRefGoogle Scholar
  30. Bravo-Osuna I, Vauthier C, Farabollini A et al (2007) Mucoadhesion mechanism of chitosan and thiolated chitosan-poly (isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials 28:2233–2243PubMedCrossRefGoogle Scholar
  31. Calvo P, Remuñan-López C, Vila-Jato JL et al (1997a) Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines. Pharmaceut Res 14:1431–1436CrossRefGoogle Scholar
  32. Calvo P, Remunan-Lopez C, Vila-Jato JL et al (1997b) Novel hydrophilic chitosan polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 63:125–132CrossRefGoogle Scholar
  33. Carreño-Gómez B, Duncan R (1997) Evaluation of the biological properties of soluble chitosan and chitosan microspheres. Int J Pharm 148:231–240CrossRefGoogle Scholar
  34. Chae SY, Son S, Lee M et al (2005) Deoxycholic acid-conjugated chitosan oligosaccharide nanoparticles for efficient gene carrier. J Control Release 109:330–344PubMedCrossRefGoogle Scholar
  35. Chan P, Kurisawa M, Chung JE et al (2007) Synthesis and characterization of chitosan-g-poly (ethylene glycol)-folate as a non-viral carrier for tumor-targeted gene delivery. Biomaterials 28:540–549PubMedCrossRefGoogle Scholar
  36. Chattopadhyay A, Mukherjee S, Raghuraman H (2002) Reverse micellar organization and dynamics: a wavelength-selective fluorescence approach. J Phys Chem B 106:13002–13009CrossRefGoogle Scholar
  37. Chen F, Zhang ZR, Huang Y (2007) Evaluation and modification of N-trimethyl chitosan chloride nanoparticles as protein carriers. Int J Pharm 336:166–173PubMedCrossRefGoogle Scholar
  38. Chen MC, Mi FL, Liao ZX et al (2013) Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules. Adv Drug Deliver Rev 65:865–879CrossRefGoogle Scholar
  39. Colonna C, Conti B, Genta I et al (2008) Non-viral dried powders for respiratory gene delivery prepared by cationic and chitosan loaded liposomes. Int J Pharm 364:108–118PubMedCrossRefGoogle Scholar
  40. Conti B, Modena T, Genta I et al (1998) Microencapsulation of cetylpyridinium chloride with a bioadhesive polymer. In: Proceedings of International symposium on control release bioact mater, pp 822–823Google Scholar
  41. Dang JM, Leong KW (2006) Natural polymers for gene delivery and tissue engineering. Adv Drug Deliver Rev 58:487–499CrossRefGoogle Scholar
  42. Davis ME (2002) Non-viral gene delivery systems. Curr Opin Biotech 13:128–131PubMedCrossRefGoogle Scholar
  43. De Smedt SC, Demeester J, Hennink WE (2000) Cationic polymer based gene delivery systems. Pharmaceut Res 17:113–126CrossRefGoogle Scholar
  44. Dev A, Binulal N, Anitha A et al (2010) Preparation of poly (lactic acid)/chitosan nanoparticles for anti-HIV drug delivery applications. Carbohydr Polym 80:833–838CrossRefGoogle Scholar
  45. Di Colo G, Zambito Y, Zaino C (2008) Polymeric enhancers of mucosal epithelia permeability: synthesis, transepithelial penetration-enhancing properties, mechanism of action, safety issues. J Pharm Sci 97:1652–1680PubMedCrossRefGoogle Scholar
  46. Dodane V, Vilivalam VD (1998) Pharmaceutical applications of chitosan. Pharm Sci Technol To 1:246–253CrossRefGoogle Scholar
  47. dong Zhu B, qing Qie Y, ling Wang J et al (2007) Chitosan microspheres enhance the immunogenicity of an Ag85B-based fusion protein containing multiple T-cell epitopes of Mycobacterium tuberculosis. Eur J Pharm Biopharm 66:318–326CrossRefGoogle Scholar
  48. Douglas KL, Piccirillo CA, Tabrizian M (2006) Effects of alginate inclusion on the vector properties of chitosan-based nanoparticles. J Control Release 115:354–361PubMedCrossRefGoogle Scholar
  49. Drogoz A, Munier S, Verrier B et al (2008) Towards biocompatible vaccine delivery systems: interactions of colloidal PECs based on polysaccharides with HIV-1 p24 antigen. Biomacromol 9:583–591CrossRefGoogle Scholar
  50. Duceppe N, Tabrizian M (2009) Factors influencing the transfection efficiency of ultra low molecular weight chitosan/hyaluronic acid nanoparticles. Biomaterials 30:2625–2631PubMedCrossRefGoogle Scholar
  51. Dutta PK, Dutta J, Tripathi V (2004) Chitin and chitosan: chemistry, properties and applications. J Sci Ind Res India 63:20–31Google Scholar
  52. Dykxhoorn DM, Novina CD, Sharp PA (2003) Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Bio 4:457–467CrossRefGoogle Scholar
  53. Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498PubMedCrossRefGoogle Scholar
  54. Erbacher P, Zou S, Bettinger T et al (1998) Chitosan-based vector/DNA complexes for gene delivery: biophysical characteristics and transfection ability. Pharmaceut Res 15:1332–1339CrossRefGoogle Scholar
  55. Felt O, Buri P, Gurny R (1998) Chitosan: a unique polysaccharide for drug delivery. Drug Dev Ind Pharm 24:979–993PubMedCrossRefGoogle Scholar
  56. Fernandez-Urrusuno R, Calvo P, Remuñán-López C et al (1999) Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharmaceut Res 16:1576–1581CrossRefGoogle Scholar
  57. Fischer S, Uetz-von Allmen E, Waeckerle-Men Y et al (2007) The preservation of phenotype and functionality of dendritic cells upon phagocytosis of polyelectrolyte-coated PLGA microparticles. Biomaterials 28:994–1004PubMedCrossRefGoogle Scholar
  58. Florindo H, Pandit S, Goncalves L et al (2008) Streptococcus equi antigens adsorbed onto surface modified poly-ɛ-caprolactone microspheres induce humoral and cellular specific immune responses. Vaccine 26:4168–4177PubMedCrossRefGoogle Scholar
  59. Ganza-Gonzalez A, Anguiano-Igea S, Otero-Espinar F et al (1999) Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide. Eur J Pharm Biopharm 48:149–155PubMedCrossRefGoogle Scholar
  60. Gao S, Dagnaes-Hansen F, Nielsen EJB et al (2009) The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Mol Ther 17:1225–1233PubMedPubMedCentralCrossRefGoogle Scholar
  61. Garcia-Fuentes M, Torres D, Alonso MJ (2005) New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin. Int J Pharm 296:122–132PubMedCrossRefGoogle Scholar
  62. Giudice EL, Campbell JD (2006) Needle-free vaccine delivery. Adv Drug Deliver Rev 58:68–89CrossRefGoogle Scholar
  63. Giunchedi P, Genta I, Conti B et al (1998) Preparation and characterization of ampicillin loaded methylpyrrolidinone chitosan and chitosan microspheres. Biomaterials 19:157–161PubMedCrossRefGoogle Scholar
  64. Glover DJ, Lipps HJ, Jans DA (2005) Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet 6:299–310PubMedCrossRefGoogle Scholar
  65. Grenha A, Seijo B, Remunán-López C (2005) Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci 25:427–437PubMedCrossRefGoogle Scholar
  66. Grenha A, Grainger CI, Dailey LA et al (2007a) Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro. Eur J Pharm Sci 31:73–84PubMedCrossRefGoogle Scholar
  67. Grenha A, Seijo B, Serra C et al (2007b) Chitosan nanoparticle-loaded mannitol microspheres: structure and surface characterization. Biomacromol 8:2072–2079CrossRefGoogle Scholar
  68. Grenha A, Remuñán-López C, Carvalho EL et al (2008) Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins. Eur J Pharm Biopharm 69:83–93PubMedCrossRefGoogle Scholar
  69. Guliyeva Ü, Öner F, Özsoy Ş et al (2006) Chitosan microparticles containing plasmid DNA as potential oral gene delivery system. Eur J Pharm Biopharm 62:17–25PubMedCrossRefGoogle Scholar
  70. Haidar ZS, Hamdy RC, Tabrizian M (2008) Protein release kinetics for core–shell hybrid nanoparticles based on the layer-by-layer assembly of alginate and chitosan on liposomes. Biomaterials 29:1207–1215PubMedCrossRefGoogle Scholar
  71. He P, Davis SS, Illum L (1999) Chitosan microspheres prepared by spray drying. Int J Pharm 187:53–65PubMedCrossRefGoogle Scholar
  72. Hosseinzadeh H, Atyabi F, Dinarvand R et al (2012) Chitosan-Pluronic nanoparticles as oral delivery of anticancer gemcitabine: preparation and in vitro study. Int J Nanomed 7:1851–1863CrossRefGoogle Scholar
  73. Howard KA, Rahbek UL, Liu X et al (2006) RNA interference in vitro and in vivo using a chitosan/siRNA nanoparticle system. Mol Ther 14:476–484PubMedCrossRefGoogle Scholar
  74. Howard KA, Paludan SR, Behlke MA et al (2009) Chitosan/siRNA nanoparticle–mediated TNF-α knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol Ther 17:162–168PubMedCrossRefGoogle Scholar
  75. Hu F-Q, Zhao M-D, Yuan H et al (2006) A novel chitosan oligosaccharide–stearic acid micelles for gene delivery: properties and in vitro transfection studies. Int J Pharm 315:158–166PubMedCrossRefGoogle Scholar
  76. Huang Y, Yeh M, Chiang C (2002) Formulation factors in preparing BTM–chitosan microspheres by spray drying method. Int J Pharm 242:239–242PubMedCrossRefGoogle Scholar
  77. Huang M, Khor E, Lim L-Y (2004) Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of molecular weight and degree of deacetylation. Pharmaceut Res 21:344–353CrossRefGoogle Scholar
  78. Huang M, Fong C-W, Khor E et al (2005) Transfection efficiency of chitosan vectors: effect of polymer molecular weight and degree of deacetylation. J Control Release 106:391–406PubMedCrossRefGoogle Scholar
  79. Huo M, Zhang Y, Zhou J et al (2010) Synthesis and characterization of low-toxic amphiphilic chitosan derivatives and their application as micelle carrier for antitumor drug. Int J Pharm 394:162–173PubMedCrossRefGoogle Scholar
  80. Hwang H-Y, Kim I-S, Kwon IC et al (2008) Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles. J Control Release 128:23–31PubMedCrossRefGoogle Scholar
  81. Illum L, Farraj NF, Davis SS (1994) Chitosan as a novel nasal delivery system for peptide drugs. Pharmaceut Res 11:1186–1189CrossRefGoogle Scholar
  82. Illum L, Jabbal-Gill I, Hinchcliffe M et al (2001) Chitosan as a novel nasal delivery system for vaccines. Adv Drug Deliver Rev 51:81–96CrossRefGoogle Scholar
  83. Iqbal M, Lin W, Jabbal-Gill I et al (2003) Nasal delivery of chitosan–DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) induces protective CTL responses in BALB/c mice. Vaccine 21:1478–1485PubMedCrossRefGoogle Scholar
  84. Ishida T, Harada M, Wang XY et al (2005) Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes. J Control Release 105:305–317PubMedCrossRefGoogle Scholar
  85. Ishii T, Okahata Y, Sato T (2001) Mechanism of cell transfection with plasmid/chitosan complexes. BBA-Biomembranes 1514:51–64PubMedCrossRefGoogle Scholar
  86. Jaganathan K, Vyas SP (2006) Strong systemic and mucosal immune responses to surface-modified PLGA microspheres containing recombinant hepatitis B antigen administered intranasally. Vaccine 24:4201–4211PubMedCrossRefGoogle Scholar
  87. Jameela S, Kumary T, Lal A et al (1998) Progesterone-loaded chitosan microspheres: a long acting biodegradable controlled delivery system. J Control Release 52:17–24PubMedCrossRefGoogle Scholar
  88. Jayakumar R, Prabaharan M, Nair S et al (2010) Novel carboxymethyl derivatives of chitin and chitosan materials and their biomedical applications. Prog Mater Sci 55:675–709CrossRefGoogle Scholar
  89. Jeong JH, Kim SW, Park TG (2007) Molecular design of functional polymers for gene therapy. Prog Polym Sci 32:1239–1274CrossRefGoogle Scholar
  90. Jiang X, Dai H, Leong KW (2006) Chitosan-g-PEG/DNA complexes deliver gene to the rat liver via intrabiliary and intraportal infusions. J Gene Med 8:477–487PubMedCrossRefGoogle Scholar
  91. Jiang HL, Kim YK, Arote R et al (2007) Chitosan-graft-polyethylenimine as a gene carrier. J Control Release 117:273–280PubMedCrossRefGoogle Scholar
  92. Kafedjiiski K, Krauland AH, Hoffer MH (2005) Synthesis and in vitro evaluation of a novel thiolated chitosan. Biomaterials 26:819–826PubMedCrossRefGoogle Scholar
  93. Karnchanajindanun J, Srisa-ard M, Baimark Y (2011) Genipin-cross-linked chitosan microspheres prepared by a water-in-oil emulsion solvent diffusion method for protein delivery. Carbohyd Polym 85:674–680CrossRefGoogle Scholar
  94. Kas HS (1997) Chitosan: properties, preparations and application to microparticulate systems. J Microencapsul 14:689–711PubMedCrossRefGoogle Scholar
  95. Kast CE, Bernkop-Schnürch A (2001) Thiolated polymers—thiomers: development and in vitro evaluation of chitosan–thioglycolic acid conjugates. Biomaterials 22:2345–2352PubMedCrossRefGoogle Scholar
  96. Kataoka K, Matsumoto T, Yokoyama M et al (2000) Doxorubicin-loaded poly (ethylene glycol)–poly(β-benzyl-l-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. J Control Release 64:143–153PubMedCrossRefGoogle Scholar
  97. Katas H, Alpar HO (2006) Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release 115:216–225PubMedCrossRefGoogle Scholar
  98. Kawashima Y, Handa T, Kasai A et al (1985) Novel method for the preparation of controlled-release theophylline granules coated with a polyelectrolyte complex of sodium polyphosphate–chitosan. J Pharm Sci 74:264–268PubMedCrossRefGoogle Scholar
  99. Kawashima Y, Handa T, Kasai A et al (1986) The effects of thickness and hardness of the coating film on the drug release rate of theophylline granules coated with chitosan-sodium tripolyphosphate complex. Chem Pharm Bull 35:78Google Scholar
  100. Kean T, Thanou M (2010) Biodegradation, biodistribution and toxicity of chitosan. Adv Drug Deliver Rev 62:3–11CrossRefGoogle Scholar
  101. Kean T, Roth S, Thanou M (2005) Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency. J Control Release 103:643–653PubMedCrossRefGoogle Scholar
  102. Kiang T, Wen J, Lim HW et al (2004) The effect of the degree of chitosan deacetylation on the efficiency of gene transfection. Biomaterials 25:5293–5301PubMedCrossRefGoogle Scholar
  103. Kim YH, Gihm SH, Park CR et al (2001) Structural characteristics of size-controlled self-aggregates of deoxycholic acid-modified chitosan and their application as a DNA delivery carrier. Bioconjugate Chem 12:932–938CrossRefGoogle Scholar
  104. Kim TH, Ihm JE, Choi YJ et al (2003) Efficient gene delivery by urocanic acid-modified chitosan. J Control Release 93:389–402PubMedCrossRefGoogle Scholar
  105. Kim TH, Jiang HL, Jere D et al (2007) Chemical modification of chitosan as a gene carrier in vitro and in vivo. Prog Polym Sci 32:726–753CrossRefGoogle Scholar
  106. Kim JH, Kim YS, Park K et al (2008) Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy. Biomaterials 29:1920–1930PubMedCrossRefGoogle Scholar
  107. Ko J, Park HJ, Hwang S et al (2002) Preparation and characterization of chitosan microparticles intended for controlled drug delivery. Int J Pharm 249:165–174PubMedCrossRefGoogle Scholar
  108. Köping-Höggård M, Mel’nikova YS, Vårum KM et al (2003) Relationship between the physical shape and the efficiency of oligomeric chitosan as a gene delivery system in vitro and in vivo. J Gene Med 5:130–141PubMedCrossRefGoogle Scholar
  109. Köping-Höggård M, Vårum K, Issa M et al (2004) Improved chitosan-mediated gene delivery based on easily dissociated chitosan polyplexes of highly defined chitosan oligomers. Gene Ther 11:1441–1452PubMedCrossRefGoogle Scholar
  110. Köpping-Höggård M, Tubulekas I, Guan H et al (2001) Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethyleneimine in vitro and after lung administration in vivo. Gene Ther 8:1108–1121CrossRefGoogle Scholar
  111. Kotzé AR, Lueβen HL, de Leeuw BJ et al (1997) N-trimethyl chitosan chloride as a potential absorption enhancer across mucosal surfaces: in vitro evaluation in intestinal epithelial cells (Caco-2). Pharmaceut Res 14:1197–1202CrossRefGoogle Scholar
  112. Kumar MNR (2000) A review of chitin and chitosan applications. React Funct Polym 46:1–27CrossRefGoogle Scholar
  113. Kumar LD, Clarke AR (2007) Gene manipulation through the use of small interfering RNA (siRNA): from in vitro to in vivo applications. Adv Drug Deliver Rev 59:87–100CrossRefGoogle Scholar
  114. Kumar M, Behera AK, Lockey RF et al (2002) Intranasal gene transfer by chitosan-DNA nanospheres protects BALB/c mice against acute respiratory syncytial virus infection. Hum Gene Ther 13:1415–1425PubMedCrossRefGoogle Scholar
  115. Kumbar SG, Aminabhavi TM (2003) Synthesis and characterization of modified chitosan microspheres: effect of the grafting ratio on the controlled release of nifedipine through microspheres. J Appl Polym Sci 89:2940–2949CrossRefGoogle Scholar
  116. Kumbar S, Kulkarni A, Aminabhavi T (2002) Crosslinked chitosan microspheres for encapsulation of diclofenac sodium: effect of crosslinking agent. J Microencapsul 19:173–180PubMedCrossRefGoogle Scholar
  117. Lavertu M, Methot S, Tran-Khanh N et al (2006) High efficiency gene transfer using chitosan/DNA nanoparticles with specific combinations of molecular weight and degree of deacetylation. Biomaterials 27:4815–4824PubMedCrossRefGoogle Scholar
  118. Lee JW, Park JH, Robinson JR (2000) Bioadhesive-based dosage forms: the next generation. J Pharm Sci 89:850–866PubMedCrossRefGoogle Scholar
  119. Lee MK, Chun SK, Choi WJ et al (2005) The use of chitosan as a condensing agent to enhance emulsion-mediated gene transfer. Biomaterials 26:2147–2156PubMedCrossRefGoogle Scholar
  120. Lee D, Zhang W, Shirley SA et al (2007) Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharmaceut Res 24:157–167CrossRefGoogle Scholar
  121. Lehr C-M, Bouwstra JA, Schacht EH et al (1992) In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm 78:43–48CrossRefGoogle Scholar
  122. Leong YS, Candau F (1982) Inverse microemulsion polymerization. J Phys Chem-US 86:2269–2271CrossRefGoogle Scholar
  123. Li S, Huang L (2000) Nonviral gene therapy: promises and challenges. Gene Ther 7:31–34PubMedCrossRefGoogle Scholar
  124. Li G, Zhuang Y, Mu Q et al (2008) Preparation, characterization and aggregation behavior of amphiphilic chitosan derivative having poly (l-lactic acid) side chains. Carbohyd Polym 72:60–66CrossRefGoogle Scholar
  125. Lim S, Forbes B, Martin G et al (2001) In vivo and in vitro characterization of novel microparticulates based on hyaluronan and chitosan hydroglutamate. AAPS Pharm Sci Tech 2:1–12CrossRefGoogle Scholar
  126. Lim MJ, Min SH, Lee JJ et al (2006) Targeted therapy of DNA tumor virus-associated cancers using virus-activated transcription factors. Mol Ther 13:899–909PubMedCrossRefGoogle Scholar
  127. Liu WG, De Yao K (2002) Chitosan and its derivatives—a promising non-viral vector for gene transfection. J Control Release 83:1–11CrossRefGoogle Scholar
  128. Liu L-S, Liu S-Q, Ng SY et al (1997) Controlled release of interleukin-2 for tumour immunotherapy using alginate/chitosan porous microspheres. J Control Release 43:65–74CrossRefGoogle Scholar
  129. Liu WG, De Yao K, Liu QG (2001) Formation of a DNA/N-dodecylated chitosan complex and salt-induced gene delivery. J Appl Polym Sci 82:3391–3395CrossRefGoogle Scholar
  130. Liu X, Howard KA, Dong M et al (2003) N-alkylated chitosan as a potential nonviral vector for gene transfection. Bioconjugate Chem 14:782–789CrossRefGoogle Scholar
  131. Liu W, Sun S, Cao Z et al (2005) An investigation on the physicochemical properties of chitosan/DNA polyelectrolyte complexes. Biomaterials 26:2705–2711PubMedCrossRefGoogle Scholar
  132. Liu X, Howard KA, Dong M et al (2007) The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing. Biomaterials 28:1280–1288PubMedCrossRefGoogle Scholar
  133. Lorenzo-Lamosa M, Remunan-Lopez C, Vila-Jato J et al (1998) Design of microencapsulated chitosan microspheres for colonic drug delivery. J Control Release 52:109–118PubMedCrossRefGoogle Scholar
  134. Lu G, Kong L, Sheng B et al (2007) Degradation of covalently cross-linked carboxymethyl chitosan and its potential application for peripheral nerve regeneration. Eur Polym J 43:3807–3818CrossRefGoogle Scholar
  135. Luisi P, Giomini M, Ma Pileni et al (1988) Reverse micelles as hosts for proteins and small molecules. BBA-Rev Biomembranes 947:209–246Google Scholar
  136. MacLaughlin FC, Mumper RJ, Wang J et al (1998) Chitosan and depolymerized chitosan oligomers as condensing carriers for in vivo plasmid delivery. J Control Release 56:259–272PubMedCrossRefGoogle Scholar
  137. Maitani Y, Soeda H, Junping W et al (2001) Modified ethanol injection method for liposomes containing β-sitosterol β-d-glucoside. J Lipos Res 11:115–125CrossRefGoogle Scholar
  138. Maitra A (1984) Determination of size parameters of water-Aerosol OT-oil reverse micelles from their nuclear magnetic resonance data. J Phys Chem-US 88:5122–5125CrossRefGoogle Scholar
  139. Mansouri S, Lavigne P, Corsi K et al (2004) Chitosan-DNA nanoparticles as non-viral vectors in gene therapy: strategies to improve transfection efficacy. Eur J Pharm Biopharm 57:1–8PubMedCrossRefGoogle Scholar
  140. Mansouri S, Cuie Y, Winnik F et al (2006) Characterization of folate-chitosan-DNA nanoparticles for gene therapy. Biomaterials 27:2060–2065PubMedCrossRefGoogle Scholar
  141. Mao HQ, Roy K, Troung-Le VL et al (2001) Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Release 70:399–421PubMedCrossRefGoogle Scholar
  142. Mao S, Germershaus O, Fischer D et al (2005a) Uptake and transport of PEG-graft-trimethyl-chitosan copolymer–insulin nanocomplexes by epithelial cells. Pharmaceut Res 22:2058–2068CrossRefGoogle Scholar
  143. Mao S, Shuai X, Unger F et al (2005b) Synthesis, characterization and cytotoxicity of poly(ethylene glycol)-graft-trimethyl chitosan block copolymers. Biomaterials 26:6343–6356PubMedCrossRefGoogle Scholar
  144. Mao S, Bakowsky U, Jintapattanakit A et al (2006) Self-assembled polyelectrolyte nanocomplexes between chitosan derivatives and insulin. J Pharm Sci 95:1035–1048PubMedCrossRefGoogle Scholar
  145. Mao Z, Ma L, Yan J et al (2007) The gene transfection efficiency of thermoresponsive N, N, N-trimethyl chitosan chloride-g-poly (N-isopropylacrylamide) copolymer. Biomaterials 28:4488–4500PubMedCrossRefGoogle Scholar
  146. Marón LB, Covas CP, Da Silveira NP et al (2007) LUVs recovered with chitosan: a new preparation for vaccine delivery. J Lipos Res 17:155–163CrossRefGoogle Scholar
  147. Mathew ME, Mohan JC, Manzoor K et al (2010) Folate conjugated carboxymethyl chitosan–manganese doped zinc sulphide nanoparticles for targeted drug delivery and imaging of cancer cells. Carbohyd Polym 80:442–448CrossRefGoogle Scholar
  148. Messai I, Lamalle D, Munier S et al (2005) Poly(D, L-lactic acid) and chitosan complexes: interactions with plasmid DNA. Colloid Surface A 255:65–72CrossRefGoogle Scholar
  149. Mi FL, Wu YY, Lin YH et al (2008) Oral delivery of peptide drugs using nanoparticles self-assembled by poly(γ-glutamic acid) and a chitosan derivative functionalized by trimethylation. Bioconjugate Chem 19:1248–1255CrossRefGoogle Scholar
  150. Mitra S, Gaur U, Ghosh P et al (2001) Tumour targeted delivery of encapsulated dextran–doxorubicin conjugate using chitosan nanoparticles as carrier. J Control Release 74:317–323PubMedCrossRefGoogle Scholar
  151. Morris KV, Chan SW-L, Jacobsen SE et al (2004) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292PubMedCrossRefGoogle Scholar
  152. Muzzarelli RA, Tanfani F, Emanuelli M et al (1982) N-(carboxymethylidene) chitosans and N-(carboxymethyl) chitosans: novel chelating polyampholytes obtained from chitosan glyoxylate. Carbohyd Res 107:199–214CrossRefGoogle Scholar
  153. Nafee N, Taetz S, Schneider M et al (2007) Chitosan-coated PLGA nanoparticles for DNA/RNA delivery: effect of the formulation parameters on complexation and transfection of antisense oligonucleotides. Nanomed-Nanotechnol 3:173–183CrossRefGoogle Scholar
  154. Nagamoto T, Hattori Y, Takayama K et al (2004) Novel chitosan particles and chitosan-coated emulsions inducing immune response via intranasal vaccine delivery. Pharmaceut Res 21:671–674CrossRefGoogle Scholar
  155. Nasti A, Zaki NM, de Leonardis P et al (2009) Chitosan/TPP and chitosan/TPP-hyaluronic acid nanoparticles: systematic optimisation of the preparative process and preliminary biological evaluation. Pharmaceut Res 26:1918–1930CrossRefGoogle Scholar
  156. Nie H, Lee LY, Tong H et al (2008) PLGA/chitosan composites from a combination of spray drying and supercritical fluid foaming techniques: new carriers for DNA delivery. J Control Release 129:207–214PubMedCrossRefGoogle Scholar
  157. Nishimura K, Nishimura SI, Seo H et al (1986) Macrophage activation with multi-porous beads prepared from partially deacetylated chitin. J Biomed Mater Res 20:1359–1372PubMedCrossRefGoogle Scholar
  158. Noureddini H, Gao X, Philkana RS (2005) Immobilized Pseudomonas cepacia lipase for biodiesel fuel production from soybean oil. Bioresource Technol 96:769–777CrossRefGoogle Scholar
  159. Ohya Y, Shiratani M, Kobayashi H et al (1994) Release behavior of 5-fluorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil coated with polysaccharides and their cell specific cytotoxicity. J Macromol Sci Pure 31:629–642CrossRefGoogle Scholar
  160. Okamoto H, Sakakura Y, Shiraki K et al (2005) Stability of chitosan–pDNA complex powder prepared by supercritical carbon dioxide process. Int J Pharm 290:73–81PubMedCrossRefGoogle Scholar
  161. Oliveira B, Santana M, Ré M (2005) Spray-dried chitosan microspheres cross-linked with d, l-glyceraldehyde as a potential drug delivery system: preparation and characterization. Braz J Chem Eng 22:353–360CrossRefGoogle Scholar
  162. Opanasopit P, Sajomsang W, Ruktanonchai U et al (2008) Methylated N-(4-pyridinylmethyl) chitosan as a novel effective safe gene carrier. Int J Pharm 364:127–134PubMedCrossRefGoogle Scholar
  163. Orienti I, Aiedeh K, Gianasi E et al (1996) Chitosan-indomethacin conjugates. effect of different substituents on the polysaccharide molecule on drug release. Arch Pharm 329:245–250CrossRefGoogle Scholar
  164. Özbaş-Turan S, Akbuǧa J, Aral C (2002) Controlled release of interleukin-2 from chitosan microspheres. J Pharm Sci 91:1245–1251PubMedCrossRefGoogle Scholar
  165. Pan Y, Y-j Li, H-y Zhao et al (2002) Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 249:139–147PubMedCrossRefGoogle Scholar
  166. Pan X, Ren W, Gu L et al (2014) Photoluminescence from chitosan for bio-imaging. Aust J Chem 67:1422–1426CrossRefGoogle Scholar
  167. Park Y, Park Y, Shin B et al (2000) Galactosylated chitosan–graft–dextran as hepatocyte-targeting DNA carrier. J Control Release 69:97–108PubMedCrossRefGoogle Scholar
  168. Park IK, Kim TH, Park YH et al (2001) Galactosylated chitosan-graft-poly (ethylene glycol) as hepatocyte-targeting DNA carrier. J Control Release 76:349–362PubMedCrossRefGoogle Scholar
  169. Park IK, Ihm JE, Park YH et al (2003) Galactosylated chitosan (GC)-graft-poly (vinyl pyrrolidone) (PVP) as hepatocyte-targeting DNA carrier: Preparation and physicochemical characterization of GC-graft-PVP/DNA complex (1). J Control Release 86:349–359PubMedCrossRefGoogle Scholar
  170. Park K, Kim JH, Nam YS et al (2007) Effect of polymer molecular weight on the tumor targeting characteristics of self-assembled glycol chitosan nanoparticles. J Control Release 122:305–314PubMedCrossRefGoogle Scholar
  171. Patil P, Bhoskar M (2014) Optimization and evaluation of spray dried chitosan nanoparticles containing doxorubicin. Int J Curr Pharm Res 6:7–15Google Scholar
  172. Patton JS (1996) Mechanisms of macromolecule absorption by the lungs. Adv Drug Deliver Rev 19:3–36CrossRefGoogle Scholar
  173. Patton JS, Fishburn CS, Weers JG (2004) The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc 1:338–344PubMedCrossRefGoogle Scholar
  174. Pillé J-Y et al (2006) Intravenous delivery of anti-RhoA small interfering RNA loaded in nanoparticles of chitosan in mice: safety and efficacy in xenografted aggressive breast cancer. Hum Gene Ther 17:1019–1026PubMedCrossRefGoogle Scholar
  175. Pitkänen L, Ruponen M, Nieminen J et al (2003) Vitreous is a barrier in nonviral gene transfer by cationic lipids and polymers. Pharmaceut Res 20:576–583CrossRefGoogle Scholar
  176. Polk A, Amsden B, De Yao K et al (1994) Controlled release of albumin from chitosan—alginate microcapsules. J Pharm Sci 83:178–185PubMedCrossRefGoogle Scholar
  177. Prasanth Koppolu B, Smith SG, Ravindranathan S et al (2014) Controlling chitosan-based encapsulation for protein and vaccine delivery. Biomaterials 35:4382–4389CrossRefGoogle Scholar
  178. Prego C, Garcia M, Torres D et al (2005) Transmucosal macromolecular drug delivery. J Control Release 101:151–162PubMedCrossRefGoogle Scholar
  179. Qi L, Xu Z, Jiang X, Li Y et al (2005) Cytotoxic activities of chitosan nanoparticles and copper-loaded nanoparticles. Bioorg Med Chem Lett 15:1397–1399PubMedCrossRefGoogle Scholar
  180. Rao SB, Sharma CP (1997) Use of chitosan as a biomaterial: studies on its safety and hemostatic potential. J Biomed Mater Res 34:21–28PubMedCrossRefGoogle Scholar
  181. Raouane M, Desmaele D, Gilbert-Sirieix M et al (2011) Synthesis, characterization, and in vivo delivery of siRNA-squalene nanoparticles targeting fusion oncogene in papillary thyroid carcinoma. J Med Chem 54:4067–4076PubMedCrossRefGoogle Scholar
  182. Read RC, Naylor SC, Potter CW et al (2005) Effective nasal influenza vaccine delivery using chitosan. Vaccine 23:4367–4374PubMedCrossRefGoogle Scholar
  183. Remaut K, Sanders NN, De Geest BG et al (2007) Nucleic acid delivery: where material sciences and bio-sciences meet. Mat Sci Eng R 58:117–161CrossRefGoogle Scholar
  184. Richardson SW, Kolbe HJ, Duncan R (1999) Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA. Int J Pharm 178:231–243PubMedCrossRefGoogle Scholar
  185. Rojanarata T, Petchsangsai M, Opanasopit P et al (2008) Methylated N-(4-N, N-dimethylaminobenzyl) chitosan for novel effective gene carriers. Eur J Pharm Biopharm 70:207–214PubMedCrossRefGoogle Scholar
  186. Rolland A (2005) Gene medicines: the end of the beginning? Adv Drug Deliver Rev 57:669–673CrossRefGoogle Scholar
  187. Romøren K, Pedersen S, Smistad G et al (2003) The influence of formulation variables on in vitro transfection efficiency and physicochemical properties of chitosan-based polyplexes. Int J Pharm 261:115–127PubMedCrossRefGoogle Scholar
  188. Roy K, Mao H-Q, Huang S-K et al (1999) Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 5:387–391PubMedCrossRefGoogle Scholar
  189. Rudzinski WE, Aminabhavi TM (2010) Chitosan as a carrier for targeted delivery of small interfering RNA. Int J Pharm 399:1–11PubMedCrossRefGoogle Scholar
  190. Ruponen M, Ylä-Herttuala S, Urtti A (1999) Interactions of polymeric and liposomal gene delivery systems with extracellular glycosaminoglycans: physicochemical and transfection studies. BBA-Biomembranes 1415:331–341PubMedCrossRefGoogle Scholar
  191. Ruponen M, Honkakoski P, Rönkkö S et al (2003) Extracellular and intracellular barriers in non-viral gene delivery. J Control Release 93:213–217PubMedCrossRefGoogle Scholar
  192. Sadeghi A, Dorkoosh F, Avadi M et al (2008a) 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. Int J Pharm 355:299–306PubMedCrossRefGoogle Scholar
  193. Sadeghi AM, Dorkoosh FA, Avadi MR et al (2008b) Permeation enhancer effect of chitosan and chitosan derivatives: comparison of formulations as soluble polymers and nanoparticulate systems on insulin absorption in Caco-2 cells. Eur J Pharm Biopharm 70:270–278PubMedCrossRefGoogle Scholar
  194. Sandri G, Bonferoni MC, Rossi S et al (2007) Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. Eur J Pharm Biopharm 65:68–77PubMedCrossRefGoogle Scholar
  195. Sanjai C, Kothan S, Gonil P et al (2014) Chitosan-triphosphate nanoparticles for encapsulation of super-paramagnetic iron oxide as an MRI contrast agent. Carbohyd Polym 104:231–237CrossRefGoogle Scholar
  196. Sarmento B, Ribeiro A, Veiga F et al (2006) Development and characterization of new insulin containing polysaccharide nanoparticles. Colloid Surface B 53:193–202CrossRefGoogle Scholar
  197. Sato T, Ishii T, Okahata Y (2001) In vitro gene delivery mediated by chitosan. Effect of pH, serum, and molecular mass of chitosan on the transfection efficiency. Biomaterials 22:2075–2080PubMedCrossRefGoogle Scholar
  198. Satoh T, Kano H, Nakatani M et al (2006) 6-Amino-6-deoxy-chitosan. Sequential chemical modifications at the C-6 positions of N-phthaloyl-chitosan and evaluation as a gene carrier. Carbohyd Res 341:2406–2413CrossRefGoogle Scholar
  199. Sayın B, Somavarapu S, Li X et al (2008) Mono-N-carboxymethyl chitosan (MCC) and N-trimethyl chitosan (TMC) nanoparticles for non-invasive vaccine delivery. Int J Pharm 363:139–148PubMedCrossRefGoogle Scholar
  200. Schmitz T, Bravo-Osuna I, Vauthier C et al (2007) Development and in vitro evaluation of a thiomer-based nanoparticulate gene delivery system. Biomaterials 28:524–531PubMedCrossRefGoogle Scholar
  201. Sezer A, Akbuǧa J (1995) Controlled release of piroxicam from chitosan beads. Int J Pharm 121:113–116CrossRefGoogle Scholar
  202. Shahbazi MA, Hamidi M, Peymani P (2008) Interaction of chitosan, a natural polymer used in nanodrug/gene delivery, with non-steroidal anti-inflammatory drugs (NSAIDs). Internet J Nanotech 2Google Scholar
  203. Shi X-Y, Tan T-W (2002) Preparation of chitosan/ethylcellulose complex microcapsule and its application in controlled release of Vitamin D 2. Biomaterials 23:4469–4473PubMedCrossRefGoogle Scholar
  204. Shi X, Du Y, Yang J et al (2006) Effect of degree of substitution and molecular weight of carboxymethyl chitosan nanoparticles on doxorubicin delivery. J Appl Polym Sci 100:4689–4696CrossRefGoogle Scholar
  205. Shiraishi S, Imai T, Otagiri M (1993) Controlled release of indomethacin by chitosan-polyelectrolyte complex: optimization and in vivo/in vitro evaluation. J Control Release 25:217–225CrossRefGoogle Scholar
  206. Shu X, Zhu K (2000) A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery. Int J Pharm 201:51–58PubMedCrossRefGoogle Scholar
  207. Shu X, Zhu K (2002) The influence of multivalent phosphate structure on the properties of ionically cross-linked chitosan films for controlled drug release. Eur J Pharm Biopharm 54:235–243PubMedCrossRefGoogle Scholar
  208. Sioud M (2005) On the delivery of small interfering RNAs into mammalian cells. Expert Opin Drug Del 2:639–651CrossRefGoogle Scholar
  209. Soane R, Hinchcliffe M, Davis S, Illum L (2001) Clearance characteristics of chitosan based formulations in the sheep nasal cavity. Int J Pharm 217:183–191PubMedCrossRefGoogle Scholar
  210. Sun S, Liu W, Cheng N et al (2005) A thermoresponsive chitosan-NIPAAm/vinyl laurate copolymer vector for gene transfection. Bioconjugate Chem 16:972–980CrossRefGoogle Scholar
  211. Szymańska E, Winnicka K (2015) Stability of chitosan—a challenge for pharmaceutical and biomedical applications. Mar Drugs 13:1819–1846PubMedPubMedCentralCrossRefGoogle Scholar
  212. Tahara K, Sakai T, Yamamoto H et al (2008) Establishing chitosan coated PLGA nanosphere platform loaded with wide variety of nucleic acid by complexation with cationic compound for gene delivery. Int J Pharm 354:210–216PubMedCrossRefGoogle Scholar
  213. Tan WB, Zhang Y (2005) Multifunctional quantum-dot-based magnetic chitosan nanobeads. Adv Mater 17:2375–2380CrossRefGoogle Scholar
  214. Tang Z-X, Qian J-Q, Shi L-E (2007) Preparation of chitosan nanoparticles as carrier for immobilized enzyme. Appl Biochem Biotech 136:77–96CrossRefGoogle Scholar
  215. Tapola NS, Lyyra ML, Kolehmainen RM et al (2008) Safety aspects and cholesterol-lowering efficacy of chitosan tablets. J Am Coll Nutr 27:22–30PubMedCrossRefGoogle Scholar
  216. Teijeiro-Osorio D, Remunán-López C, Alonso MJ (2008) New generation of hybrid poly/oligosaccharide nanoparticles as carriers for the nasal delivery of macromolecules. Biomacromol 10:243–249CrossRefGoogle Scholar
  217. Teijeiro-Osorio D, Remuñán-López C, Alonso MJ (2009) Chitosan/cyclodextrin nanoparticles can efficiently transfect the airway epithelium in vitro. Eur J Pharm Biopharm 71:257–263PubMedCrossRefGoogle Scholar
  218. Thanoo BC, Sunny M, Jayakrishnan A (1992) Cross-linked Chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals. J Pharm Pharmacol 44:283–286PubMedCrossRefGoogle Scholar
  219. Thanou M, Florea B, Langemeyer M et al (2000) N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats). Pharmaceut Res 17:27–31CrossRefGoogle Scholar
  220. Thanou M, Nihot M, Jansen M et al (2001) 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 90:38–46PubMedCrossRefGoogle Scholar
  221. Thanou M, Florea B, Geldof M et al (2002) Quaternized chitosan oligomers as novel gene delivery vectors in epithelial cell lines. Biomaterials 23:153–159PubMedCrossRefGoogle Scholar
  222. Thurmond KB, Kowalewski T, Wooley KL (1996) Water-soluble knedel-like structures: the preparation of shell-cross-linked small particles. J Am Chem Soc 118:7239–7240CrossRefGoogle Scholar
  223. Tian J, Yu J, Sun X (2008) Chitosan microspheres as candidate plasmid vaccine carrier for oral immunisation of Japanese flounder (Paralichthys olivaceus). Vet Immunol Immunop 126:220–229CrossRefGoogle Scholar
  224. Tokumitsu H, Ichikawa H, Fukumori Y (1999) Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture therapy of cancer: preparation by novel emulsion-droplet coalescence technique and characterization. Pharmaceut Res 16:1830–1835CrossRefGoogle Scholar
  225. Ubaidulla U, Khar R, Ahmad F et al (2009) Optimization of chitosan succinate and chitosan phthalate microspheres for oral delivery of insulin using response surface methodology. Pharm Dev Technol 14:99–108CrossRefGoogle Scholar
  226. Van Der Lubben I, Konings F, Borchard G et al (2001a) In vivo uptake of chitosan microparticles by murine Peyer’s patches: visualization studies using confocal laser scanning microscopy and immunohistochemistry. J Drug Target 9:39–47CrossRefGoogle Scholar
  227. Van der Lubben I, Verhoef J, Van Aelst A et al (2001b) Chitosan microparticles for oral vaccination: preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches. Biomaterials 22:687–694PubMedCrossRefGoogle Scholar
  228. Van der Merwe S, Verhoef J, Verheijden J et al (2004) Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs. Eur J Pharm Biopharm 58:225–235PubMedCrossRefGoogle Scholar
  229. Vila A, Sánchez A, Janes K et al (2004) Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice. Eur J Pharm Biopharm 57:123–131PubMedCrossRefGoogle Scholar
  230. Wang X, Zheng C, Wu Z et al (2009) Chitosan-NAC nanoparticles as a vehicle for nasal absorption enhancement of insulin. J Biomed Mater Res B 88:150–161Google Scholar
  231. Wang W, Jiang X, Chen K (2012) Lanthanide-doped chitosan nanospheres as cell nuclei illuminator and fluorescent nonviral vector for plasmid DNA delivery. Dalton T 41:490–497CrossRefGoogle Scholar
  232. Weecharangsan W, Opanasopit P, Ngawhirunpat T et al (2008) Evaluation of chitosan salts as non-viral gene vectors in CHO-K1 cells. Int J Pharm 348:161–168PubMedCrossRefGoogle Scholar
  233. Win PP, Shin-Ya Y, Hong K-J et al (2003) Formulation and characterization of pH sensitive drug carrier based on phosphorylated chitosan (PCS). Carbohyd Polym 53:305–310CrossRefGoogle Scholar
  234. Witschi C, Mrsny RJ (1999) In vitro evaluation of microparticles and polymer gels for use as nasal platforms for protein delivery. Pharmaceut Res 16:382–390CrossRefGoogle Scholar
  235. Wong K, Sun G, Zhang X et al (2006) PEI-g-chitosan, a novel gene delivery system with transfection efficiency comparable to polyethylenimine in vitro and after liver administration in vivo. Bioconjugate Chem 17:152–158CrossRefGoogle Scholar
  236. Xu Y, Du Y (2003) Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles. Int J Pharm 250:215–226PubMedCrossRefGoogle Scholar
  237. Xu S, Dong M et al (2007) Direct force measurements between siRNA and chitosan molecules using force spectroscopy. Biophys J 93:952–959Google Scholar
  238. Yamada K, Odomi M, Okada N et al (2005) Chitosan oligomers as potential and safe absorption enhancers for improving the pulmonary absorption of interferon-α in rats. J Pharm Sci 94:2432–2440PubMedCrossRefGoogle Scholar
  239. Yamamoto H, Kuno Y, Sugimoto S et al (2005) Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. J Control Release 102:373–381PubMedCrossRefGoogle Scholar
  240. Yang M et al (2007) Characterisation of salmon calcitonin in spray-dried powder for inhalation: effect of chitosan. Int J Pharm 331:176–181PubMedCrossRefGoogle Scholar
  241. Yang Y, Wang S, Wang Y et al (2014) Advances in self-assembled chitosan nanomaterials for drug delivery. Biotechnol Adv 32:1301–1316PubMedCrossRefGoogle Scholar
  242. Yao K-D, Peng T, Yin Y-J et al (1995) Microcapsules/microspheres related to chitosan. J Macromol Sci-Pol R 35:155–180CrossRefGoogle Scholar
  243. Yao Z, Zhang C, Ping Q et al (2007) A series of novel chitosan derivatives: synthesis, characterization and micellar solubilization of paclitaxel. Carbohyd Polym 68:781–792CrossRefGoogle Scholar
  244. Ye S, Wang C, Liu X et al (2006) New loading process and release properties of insulin from polysaccharide microcapsules fabricated through layer-by-layer assembly. J Control Release 112:79–87PubMedCrossRefGoogle Scholar
  245. Yin L, Ding J, He C et al (2009) Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials 30:5691–5700PubMedCrossRefGoogle Scholar
  246. Yokoyama M, Fukushima S, Uehara R et al (1998) Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. J Control Release 50:79–92PubMedCrossRefGoogle Scholar
  247. Yoksan R, Akashi M (2009) Low molecular weight chitosan-g-l-phenylalanine: preparation, characterization, and complex formation with DNA. Carbohyd Polym 75:95–103CrossRefGoogle Scholar
  248. Yoo HS, Lee JE, Chung H et al (2005) Self-assembled nanoparticles containing hydrophobically modified glycol chitosan for gene delivery. J Control Release 103:235–243PubMedCrossRefGoogle Scholar
  249. Zeng R, Guo K, Wang Z et al (2012) Synthesis and self-assembly of biomimetic phosphorylcholine-bound chitosan derivatives. React Funct Polym 72:745–751CrossRefGoogle Scholar
  250. Zhang H, Oh M, Allen C et al (2004) Monodisperse chitosan nanoparticles for mucosal drug delivery. Biomacromol 5:2461–2468CrossRefGoogle Scholar
  251. Zhang W et al (2005) Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med 11:56–62PubMedCrossRefGoogle Scholar
  252. Zhang C, Ding Y, Yu LL et al (2007a) Polymeric micelle systems of hydroxycamptothecin based on amphiphilic N-alkyl-N-trimethyl chitosan derivatives. Colloid Surface B 55:192–199CrossRefGoogle Scholar
  253. Zhang S, Zhao B, Jiang H et al (2007b) Cationic lipids and polymers mediated vectors for delivery of siRNA. J Control Release 123:1–10PubMedCrossRefGoogle Scholar
  254. Zhang Y, Chen J, Zhang Y et al (2007c) A novel PEGylation of chitosan nanoparticles for gene delivery. Biotechnol Appl Bioc 46:197–204CrossRefGoogle Scholar
  255. Zhang X, Teng D, Wu Z et al (2008a) PEG-grafted chitosan nanoparticles as an injectable carrier for sustained protein release. J Mater Sci-Mater M 19:3525–3533CrossRefGoogle Scholar
  256. Zhang X, Zhang H, Wu Z et al (2008b) Nasal absorption enhancement of insulin using PEG-grafted chitosan nanoparticles. Eur J Pharm Biopharm 68:526–534PubMedCrossRefGoogle Scholar
  257. Zhao H, Wu B, Wu H et al (2006a) Protective immunity in rats by intranasal immunization with Streptococcus mutans glucan-binding protein D encapsulated into chitosan-coated poly (lactic-co-glycolic acid) microspheres. Biotechnol Lett 28:1299–1304PubMedCrossRefGoogle Scholar
  258. Zhao X, Yu S-B, Wu F-L et al (2006b) Transfection of primary chondrocytes using chitosan-pEGFP nanoparticles. J Control Release 112:223–228PubMedCrossRefGoogle Scholar
  259. Zheng Y, Cai Z, Song X et al (2009) Preparation and characterization of folate conjugated N-trimethyl chitosan nanoparticles as protein carrier targeting folate receptor: in vitro studies. J Drug Target 17:294–303PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Chemical EngineeringInstitute of Chemical TechnologyMumbaiIndia
  2. 2.Department of Pharmaceutical Science and TechnologyInstitute of Chemical TechnologyMumbaiIndia

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