Pharmaceutical Research

, Volume 29, Issue 4, pp 943–952 | Cite as

The Counterbalanced Effect of Size and Surface Properties of Chitosan-Coated poly(isobutylcyanoacrylate) Nanoparticles on Mucoadhesion Due to Pluronic F68 Addition

  • Bénédicte Petit
  • Kawthar Bouchemal
  • Christine Vauthier
  • Madeleine Djabourov
  • Gilles Ponchel
Research Paper



To evaluate of the effect of size and surface characteristics of poly(isobutylcyanoacrylate) nanoparticles coated with pluronic F68 and thiolated chitosan on mucoadhesion.


Nanoparticles were obtained by radical emulsion polymerization in presence of different amounts of F68 (0–4%w/v). Mucoadhesion was ex vivo evaluated by applying nanoparticle suspension on rat intestinal mucosa and quantifying the amount of attached nanoparticles after incubation.


F68 unimers added in the polymerization medium allowed decreasing nanoparticle size from 251 to 83 nm, but resulted in nanoparticle surface modification. The amount of thiolated chitosan onto nanoparticle surface was decreased resulting in lower thiol groups and zeta potential. Consequently, the decrease of nanoparticle hydrodynamic diameter resulted in eight-fold-increase of the number of nanoparticles attached to the mucosa but a significant decrease of the weight of attached nanoparticles was observed. This unexpected result was due to a decrease of the amount of chitosan and thiolated chitosan available to interact with mucus upon addition of F68 in the polymerization medium.


Addition of F68 should not be recommended to improve the amount of mucoadherent nanoparticles. Further studies could allow understanding if the low amount of small size nanoparticles could be able to improve oral bioavailability.


chitosan mucoadhesion nanoparticles pluronic F68 poly(isobutylcyanoacrylate) 



The authors want to thank Dr. K. Broadley from Henkel Biomedical (Ireland) for his kindness in providing the isobutylcyanoacrylate monomer, the Department of Organic Chemistry (Biocis UMR CNRS 8076), Faculty of Pharmacy, University Paris-Sud (Châtenay-Malabry, France) for their help in the synthesis of 2- iminothiolane.


  1. 1.
    Agüeros M, Ruiz-Gatón L, Vauthier C, Bouchemal K, Espuelas S, Ponchel G, et al. Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improves the oral permeability of paclitaxel. Eur J Pharm Biopharm. 2009;38(4):405–13.Google Scholar
  2. 2.
    Sarmento B, Ribeiro A, Veiga F, Ferreira D, Neufeld R. Oral bioavailability of insulin contained in polysaccharide nanoparticles. Biomacromolecules. 2007;8:3054–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Mc Clean S, Prosser E, Meehan E, O’Malley D, Clarke N, Ramtoola Z, et al. Binding and uptake of biodegradable poly-DL-lactide micro- and nanoparticles in intestinal epithelia. Eur J Pharm Sci. 1998;6:153–63.CrossRefGoogle Scholar
  4. 4.
    Galindo-Rodriguez SA, Allemann E, Fessi H, Doelker E. Polymeric nanoparticles for oral delivery of drugs and vaccines: a critical evaluation of in vivo studies. Crit Rev Ther Drug Carr Syst. 2005;22:419–64.Google Scholar
  5. 5.
    Ponchel G, Irache J. Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv Drug Deliv Rev. 1998;34:191–219.PubMedCrossRefGoogle Scholar
  6. 6.
    Woodley J. Bioadhesion: new possibilities for drug administration? Clin Pharmacokinet. 2001;40:77–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Bravo-Osuna I, Schmitz T, Bernkop-Schnürch A, Vauthier C, Ponchel G. Elaboration and characterization of thiolated chitosan-coated acrylic nanoparticles. Int J Pharm. 2006;316:170–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Bouchemal K, Ponchel G, Mazzaferro S, Campos-Requena V-H, Gueutin C, Palmieri G-F, et al. A new approach to determine loading efficiency of Leu-enkephalin in poly(isobutylcyanoacrylate) nanoparticles coated with thiolated chitosan. J Drug Del Sci Tech. 2008;18(6):392–7.Google Scholar
  9. 9.
    Mazzaferro S, Bouchemal K, Gallard J-F, Iorga BI, Cheron M, Gueutin C, et al. Bivalent sequantial binding of docetaxel to methyl-β-cyclodextrin. Int J Pharm. 2011; doi: 10.1016/j.ijp.2011.06.034.
  10. 10.
    Sajeesh S, Bouchemal K, Sharma CP, Vauthier C. Surface functionalized polymethacrylate acid based hydrogel microparticles for oral drug delivery. Eur J Pharm Biopharm. 2010;74(2):209–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Sajeesh S, Bouchemal K, Vauthier C, Sharma CP. Cyclodextrin complexed insulin encapsulated hydrogel microparticles: an oral delivery system for insulin. J Control Release. 2010;147:377–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Bernkop-Schnürch A, Kast CE, Guggi D. Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems. J Control Release. 2003;93:95–103.PubMedCrossRefGoogle Scholar
  13. 13.
    Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tiussues. Adv Drug Deliv Rev. 2009;61:158–71.PubMedCrossRefGoogle Scholar
  14. 14.
    Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. 2009;61:75–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Lai S, O’hanlon E, Harrold S, Man ST, Wang YY, Cone R, et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. PNAS. 2007;104(5):1482–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. PNAS. 2009;106(46):19268–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Seijo B, Fattal E, Roblot-Treupel L, Couvreur P. design of nanoparticles of less than 50 nm diameter: preparation, characterization and drug loading. Int J Pharm. 1990;62:1–7.CrossRefGoogle Scholar
  18. 18.
    De Martimprey H, Bertrand J-R, Fusco A, Santoro M, Couvreur P, Vauthier C, et al. siRNA nanoformulation against the ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma. Nucleic Acids Res. 2008;36:e2.PubMedCrossRefGoogle Scholar
  19. 19.
    Huang M, Khor E, Lim LY. Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of molecular weight and degree of deacetylation. Pharm Res. 2004;21:344–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Hirai A, Odani H, Nakajima A. Determination of degree of deacetylation of chitosan by 1H NMR spectroscopy. Polym Bull. 1991;26:87–94.CrossRefGoogle Scholar
  21. 21.
    Bravo-Osuna I, Ponchel G, Vauthier C. Tuning of shell and core characteristics of chitosan-decorated acrylic nanoparticles. Eur J Pharm Sci. 2007;30:143–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Chauvierre C, Labarre D, Couvreur P, Vauthier C. Radical polymerization of alkylcyanoacrylates initiated by the redox system dextran-cerium (IV) under acidic aqueous conditions. Macromolecules. 2003;36:6018–27.CrossRefGoogle Scholar
  23. 23.
    Bravo-Osuna I, Teutonico D, Arpicco S, Vauthier C, Ponchel G. Characterization of chitosan thiolation and application to thiol quantifictaion onto nanoparticle surface. Int J Pharm. 2007;340:173–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Leo C, Contado F, Bortolotti B, Pavan A, Scatturin G, Tosi S, et al. Nanoparticle formulation may affect the stabilization of an antiischemic prodrug. Int J Pharm. 2006;307(1):103–13.PubMedCrossRefGoogle Scholar
  25. 25.
    PhamTrong LC, Djabourov M, Ponton A. Mechanisms of micellization and rheology of PEO-PPO-PEO triblock copolymers with various architectures. J Colloid Interf Sci. 2008;328:278–87.CrossRefGoogle Scholar
  26. 26.
    Durrer C, Irache JM, Puisieux F, Duchene D, Ponchel G. Mucoadhesion of latexes. II. Adsorption isotherms and desorption studies. Pharm Res. 1994;11:680–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Durrer C, Irache JM, Puisieux F, Duchene D, Ponchel G. Mucoadhesion of latexes. I. Analytical methods and kinetic studies. Pharm Res. 1994;11:674–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Pinto-Alphandary H, Balland O, Couvreur P. A new method to isolate poly(alkylcyanoacrylate) nanoparticle preparations. J Drug Target. 1995;3:167–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Bouchemal K, Agnely F, Koffi A, Ponchel G. A concise analysis of the effect of temperature and propanediol-1,2 on Pluronic F-127 micellization using isothermal titration microcalorimetry. J Colloid Interf Sci. 2009;338:169–76.CrossRefGoogle Scholar
  30. 30.
    Roques C, Bouchemal K, Ponchel G, Fromes Y. Parameters affecting organization and transfection efficiency of amphiphilic copolymer/DNA carriers. J Control Release. 2009;138(1):71–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Aka-Any-Grah A, Bouchemal K, Koffi A, Agnely F, Zhang M, Djabourov M, et al. Formulation of mucoadhesive vaginal hydrogels insensitive to dilution with vaginal fluids. Eur J Pharm Biopharm. 2010;76:296–303.PubMedCrossRefGoogle Scholar
  32. 32.
    Bahadur P, Li P, Almgren M, Brown W. Effect of potassium fluoride on the micellar behavior of pluronic F-68 in aqueous solution. Langmuir. 1992;8:1903–7.CrossRefGoogle Scholar
  33. 33.
    Zhou Z, Chu B. Light-scattering study on the association behavior of triblock polymers of ethylene oxide and propylene oxide in aqueous solution. J Colloid Interf Sci. 1988;126(1):171–80.CrossRefGoogle Scholar
  34. 34.
    Nakashima K, Anzai T, Fujimoto Y. Fluorescence studies on the properties of a pluronic F68 Micelle. Langmuir. 1994;10:658–61.CrossRefGoogle Scholar
  35. 35.
    Bravo-Osuna I, Vauthier C, Farabollini A, Palmieri G-F, Ponchel G. Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutylcyanoacrylate) core-shell nanoparticles. Biomaterials. 2007;28:2233–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Hillery AM, Florence AT. The effect of adsorbed poloxamer 188 and 407 surfactants on the intestinal uptake of 60-nm polystyrene particles after oral administration in the rat. Int J Pharm. 1996;132:123–30.CrossRefGoogle Scholar
  37. 37.
    Kreuter J, Muller U, Munz K. Quantitative and microautoradiographic study on mouse intestinal distribution of polycyanoacrylate nanoparticles. Int J Pharm. 1989;55:39–45.CrossRefGoogle Scholar
  38. 38.
    Bertholon I, Ponchel G, Labarre D, Couvreur P, Vauthier C. Bioadhesive properties of poly(alkylcyanoacrylate) nanoparticles coated with polysaccharide. J Nanosci Nanotechno. 2006;6:1–8.CrossRefGoogle Scholar
  39. 39.
    Sogias IA, Williams AC, Khutoryanskiy VV. Why is chitosan mucoadhesive? Biomacromolecules. 2008;9:1837–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Bénédicte Petit
    • 1
  • Kawthar Bouchemal
    • 1
    • 3
  • Christine Vauthier
    • 1
  • Madeleine Djabourov
    • 2
  • Gilles Ponchel
    • 1
  1. 1.Université Paris-SudUMR CNRS 8612Châtenay-MalabryFrance
  2. 2.Laboratoire de Physique ThermiqueESPCI-ParisTechParis Cedex 05France
  3. 3.Univ Paris-Sud, UMR CNRS 8612Physico-chemistry, Pharmacotechny & BiopharmacyChâtenay-MalabryFrance

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