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Modified Cellulose Nanocrystal for Vitamin C Delivery


Cellulose nanocrystal grafted with chitosan oligosaccharide (CNC-CSOS) was used to encapsulate vitamin C and prepare CNCS/VC complexes using tripolyphosphte via ionic complexation. The stability of vitamin C and the antioxidant activity of the CNCS/VC complexes were elucidated. The formation of the complex was confirmed using DSC and UV–vis spectrophotometry, and TEM was used to study the morphology of the complexes. The encapsulation efficiency of vitamin C at pH 3 and 5 was 71.6% ± 6.8 and 91.0 ± 1.0, respectively. Strong exothermic peaks observed in isothermal titration calorimetric (ITC) studies at pH 5 could be attributed to additional electrostatic interactions between CNC-CSOS and vitamin C at pH 5. The in vitro release of vitamin C from CNCS/VC complexes showed a sustained release of up to 20 days. The vitamin C released from CNCS/VC complex displayed higher stability compared with the control vitamin C solution, and this was also confirmed from the ITC thermograms. CNC-CSOS possessed a higher scavenging activity and faster antioxidant activity compared with its precursors, i.e., oxidized CNC and CSOS and their physical mixtures. Complexing vitamin C into CNC-CSOS particles yielded a dynamic antioxidant agent, where the vitamin C is released over time and displayed sustained antioxidant properties. Therefore, CNCS/VC can potentially be used in cosmeceutical applications as topical formulations.

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  1. 1.

    Manela-Azulay M, Bagatin E. Cosmeceuticals vitamins. Clin Dermatol. 2009;27:469–74.

    Article  PubMed  Google Scholar 

  2. 2.

    Darr D, Combs S, Dunston S, Manning T, Pinnell S. Topical vitamin C protects porcine skin from ultraviolet radiation-induced damage. Br J Dermatol. 1992;127:247–53.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Burke KE. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther. 2007;20:314–21.

    Article  PubMed  Google Scholar 

  4. 4.

    Pinnell SR, Yang H, Omar M, Riviere NM, Debuys HV, Walker LC, et al. Topical l-ascorbic acid : percutaneous absorption studies. Am Soc Dermatol Surg, Inc. 2001;27:137–42.

    CAS  Google Scholar 

  5. 5.

    Farris PK. Topical vitamin C. A useful agent for treating photoaging and other dermatologic conditions. Am Soc Dermatol Surg. 2005;31:814–8.

    Article  CAS  Google Scholar 

  6. 6.

    Ochiai Y, Kaburagi S, Obayashi K, Ujiie N, Hashimoto S, Okano Y, et al. A new lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), prevents UV-induced skin pigmentation through its anti-oxidative properties. J Dermatol Sci. 2006;44:37–44.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Murad S, Grove D, Lindberg KA, Reynolds G, Sivarajah A, Pinnell SR. Regulation of collagen synthesis by ascorbic acid biochemistry. Proc Natl Acad Sci USA. 1981;78:2879–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 8.

    Piao H, Kamiya N, Cui F, Goto M. Preparation of a solid-in-oil nanosuspension containing l-ascorbic acid as a novel long-term stable topical formulation. Int J Pharm. 2011;420:156–60.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Davey MW, Van Montagu M, Inze D, Sanmartin M, Kanellis A, Smirnoff N, et al. Review plant l-ascorbic acid : chemistry, function, metabolism, bioavailability and effects of processing. J Sci Food Agric. 2000;860:825–60.

    Article  Google Scholar 

  10. 10.

    Ogiri Y, Sun F, Hayami S, Fujimura A, Yahahoto K, Yaita M, et al. Very low vitamin C activity of orally administered l-dehydroascorbic acid. J Agric Food Chem. 2002;50:227–9.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Simpson GLW, Ortwerth BJ. The non-oxidative degradation of ascorbic acid at physiological conditions. Biochim Biophys Acta. 2000;1501:12–24.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Idson B. Vitamins and the skin. Cosmet Toilet. 1993;108:79–94.

    Google Scholar 

  13. 13.

    Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Release. 2001;70:399–421.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Rånby G. Fibrous macromolecular systems cellulose and muscle, the colloidal properties of cellulose micelles. Discuss Farday Soc. 1951;IV:158–64.

    Article  Google Scholar 

  15. 15.

    Azizi Samir MAS, Alloin F, Dufresne A. Review of recent research into cellulosic whiskers, their properties and their application in nanocomposite field. Biomacromolecules. 2005;6:612–26.

    Article  PubMed  Google Scholar 

  16. 16.

    De Souza Lima MM, Borsali R. Rodlike cellulose microcrystals: structure, properties, and applications. Macromol Rapid Commun. 2004;25:771–87.

    Article  Google Scholar 

  17. 17.

    Sonia TA, Sharma CP. Chitosan and its derivatives for drug delivery perspective. Advanced polymer sciences. Berlin Heidelberg: Springer-Verlag; 2011. p. p. 23–54.

    Google Scholar 

  18. 18.

    Xie W, Xu P, Liu Q. Antioxidant activity of water-soluble chitosan derivatives. Bioorg Med Lett. 2001;11:1699–701.

    Article  CAS  Google Scholar 

  19. 19.

    Yen M-T, Yang J-H, Mau J-L. Antioxidant properties of chitosan from crab shells. Carbohydr Polym. 2008;74:840–4.

    Article  CAS  Google Scholar 

  20. 20.

    Chae SY, Son S, Lee M, Jang M-K, Nah J-W. Deoxycholic acid-conjugated chitosan oligosaccharide nanoparticles for efficient gene carrier. J Control Release. 2005;109:330–44.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Xing R, Liu S, Guo Z, Yu H, Wang P, Li C, et al. Relevance of molecular weight of chitosan and its derivatives and their antioxidant activities in vitro. Bioorg Med Chem. 2005;13:1573–7.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Akhlaghi SP, Berry RC, Tam KC. Surface modification of cellulose nanocrystal with chitosan oligosaccharide for drug delivery applications. Cellulose. 2013;20:1747–64.

    Article  CAS  Google Scholar 

  23. 23.

    Janes KA, Calvo P, Alonso MJ. Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Deliv Rev. 2001;47:83–97.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Cho Y, Kim JT, Park HJ. Size-controlled self-aggregated N-acyl chitosan nanoparticles as a vitamin C carrier. Carbohydr Polym. 2012;88:1087–92.

    Article  CAS  Google Scholar 

  25. 25.

    Jang II K, Lee HG. Stability of chitosan nanoparticles for l-ascorbic acid during heat treatment in aqueous solution. J Agric Food Chem. 2008;56:1936–41.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Alishahi A, Mirvaghefi A, Tehrani MR, Farahmand H, Koshio S, Dorkoosh FA, et al. Chitosan nanoparticle to carry vitamin C through the gastrointestinal tract and induce the non-specific immunity system of rainbow trout (Oncorhynchus mykiss). Carbohydr Polym. 2011;86:142–6.

    Article  CAS  Google Scholar 

  27. 27.

    Saito T, Isogai A. TEMPO-mediated oxidation of native cellulose. The effect of oxidation conditions on chemical and crystal structures of the water-insoluble fractions. Biomacromolecules. 2004;5:1983–9.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Bulpitt P, Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res [Internet]. 1999;47(2):152–69.

    Article  CAS  Google Scholar 

  29. 29.

    Azzam F, Heux L, Putaux J-L, Jean B. Preparation by grafting onto, characterization, and properties of thermally responsive polymer-decorated cellulose nanocrystals. Biomacromolecules. 2010;11:3652–9.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Shimada K, Fujikawa K, Yahara K, Nakamurat T. Antioxidative properties of xanthan. J Agric Food Chem. 1992;40:945–8.

    Article  CAS  Google Scholar 

  31. 31.

    Brand-Williams W, Cuvelier ME, Berset C. Use of a free radical method to evaluate antioxidant activity. Leb Wiss U Technol. 1995;30:25–30.

    Article  Google Scholar 

  32. 32.

    Tam J, Liu J, Yao Z. Effect of microstructure on the antioxidant properties of fullerene polymer solutions. RSC Adv. 2013;3:4622–7.

    Article  CAS  Google Scholar 

  33. 33.

    Patil P, Chavanke D, Wagh M. A review on ionotropic gelation method: novel approach for controlled gastroretentive gelispheres. Int J Pharm Pharm Sci. 2012;4:27–32.

    CAS  Google Scholar 

  34. 34.

    Lim LY, Wan LSC, Thai PY. Chitosan microspheres prepared by emulsification and ionotropic gelation. Drug Dev Ind Pharm. 1997;23:981–5.

    Article  CAS  Google Scholar 

  35. 35.

    Desai KGH, Park HJ. Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying. J Microencapsul. 2005;22:179–92.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Capuzzi G, Nostro PL, Kulkarni K, Fernandez JE. Mixtures of stearoyl-6-O-ascorbic acid and r-tocopherol : a monolayer study at the gas/water interface. Langmuir. 1996;12:3957–63.

    Article  CAS  Google Scholar 

  37. 37.

    Dikusar EA, Kozlov NG, Melnichuk LA. Salts of l-ascorbic acid with certain substituted amines and triphenylphosphine. Chem Nat Compd. 2004;40:406–7.

    Article  CAS  Google Scholar 

  38. 38.

    Tian XL, Tian DF, Wang ZY, Mo FK. Synthesis and evaluation of chitosan–vitamin C complex. Indian J Pharm Sci. 2009;71:371–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. 39.

    Xiaolin T, Dafeng T, Zhongyan W, Fengkui M. Synthesis and evaluation of chitosan–vitamin C complexes. J Appl Polym Sci. 2009;114:2986–91.

    Article  Google Scholar 

  40. 40.

    Park S-I, Zhao Y. Incorporation of a high concentration of mineral or vitamin into chitosan-based films. J Agric Food Chem. 2004;52:1933–9.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Curcio M, Puoci F, Iemma F, Parisi OI, Cirillo G, Spizzirri UG, et al. Covalent insertion of antioxidant molecules on chitosan by a free radical grafting procedure. J Agric Food Chem. 2009;57:5933–8.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Alishahi A, Mirvaghefi A, Tehrani MR, Farahmand H, Shojaosadati SA, Dorkoosh FA, et al. Shelf life and delivery enhancement of vitamin C using chitosan nanoparticles. Food Chem. 2011;126:935–40.

    Article  CAS  Google Scholar 

  43. 43.

    Kasimova MR. On the temperature dependence of complex formation between chitosan and proteins. Biomacromolecules. 2011;12:2534–43.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Molyneux P. The use of the stable free radical diphenylpicryl- hydrazyl ( DPPH ) for estimating antioxidant activity. Songklanakarin J Sci Technol. 2004;26:211–9.

    CAS  Google Scholar 

  45. 45.

    Chen SK, Tsai ML, Huang JR, Chen RH. In vitro antioxidant activities of low-molecular-weight polysaccharides with various functional groups. Agric Food Chem. 2009;57:2699–704.

    Article  CAS  Google Scholar 

  46. 46.

    Sanchez-Moreno C. Review: methods used to evaluate the free radical scavenging activity in foods and biological systems. Food Sci Technol Int. 2002;8:121–37.

    Article  CAS  Google Scholar 

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We wish to acknowledge FPInnovations and Celluforce Inc. for providing the cellulose nanocrystals, and the research funding from Celluforce and AboraNano facilitated the research on CNC. We would also like to thank Moin Ahmed and Anthony Wang for their assistance with the antioxidant studies. S. P. Akhlaghi acknowledges César Brinatti for his valuable discussion on ITC. K. C. Tam wishes to acknowledge funding from CFI and NSERC.

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Correspondence to Kam Chiu Tam.

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Akhlaghi, S.P., Berry, R.M. & Tam, K.C. Modified Cellulose Nanocrystal for Vitamin C Delivery. AAPS PharmSciTech 16, 306–314 (2015).

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  • cellulose nanocrystals
  • chitosan oligosaccharide
  • controlled release
  • vitamin C antioxidant activity