DPPC/poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) chimeric nanostructures as potential drug nanocarriers

  • Natassa Pippa
  • Eleni Kaditi
  • Stergios Pispas
  • Costas Demetzos
Research Paper


In this study, we report on the self assembly behavior and on stability studies of mixed (chimeric) nanosystems consisting of dipalmitoylphosphatidylcholine (DPPC) and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymer in aqueous media and in fetal bovine serum (FBS). A gamut of light scattering techniques and fluorescence spectroscopy were used in order to extract information on the size and morphological characteristics of the nanoassemblies formed, as a function of gradient block copolymer content, as well as temperature. The hydrodynamic radii (Rh) of nanoassemblies decreased in the process of heating up to 50 °C, while the fractal dimension (df) values, also increased. Indomethacin was successfully incorporated into these chimeric nanocarriers. Drug release was depended on the components ratio. The present studies show that there are a number of parameters that can be used in order to alter the properties of chimeric nanosystems, and this is advantageous to the development of “smart” nanocarriers for drug delivery.


Chimeric nanocarriers Self-assembly Gradient block copolymer Fractal dimension Stealth nanocarriers Morphology 

Supplementary material

11051_2013_1685_MOESM1_ESM.docx (107 kb)
Supplementary material 1 (DOCX 107 kb)


  1. Adams N, Schubert U (2007) Poly(2-oxazolines) in biological and biomedical application contexts. Adv Drug Deliv Rev 59:1504–1520CrossRefGoogle Scholar
  2. Adams ML, Lavasanifar A, Kwon GS (2003) Amphiphilic block copolymers for drug delivery. J Pharm Sci 92(7):1343–1355CrossRefGoogle Scholar
  3. Amado E, Blume A, Kressler J (2009) Novel non-ionic block copolymers tailored for interaction with phospholipids. React Funct Polym 69:450–456CrossRefGoogle Scholar
  4. Antunes FE, Marques EF, Miquel MG, Lindman B (2009) Polymer-vesicle association. Adv Colloid Interface Sci 147–148:18–35CrossRefGoogle Scholar
  5. Arnida Janát-Amsbury MM, Ray A, Peterson CM, Chandehari H (2011) Geometry and surface characteristics of gold nanoparticles influence their distribution and uptake by macrophages. Eur J Pharm Biopharm 77:417–423CrossRefGoogle Scholar
  6. Balmert SC, Little SR (2012) Biomimetic delivery with micro- and nanoparticles. Adv Mater 24:3757–3778CrossRefGoogle Scholar
  7. Bangham AD, Standish MM, Watkins JC (1965) Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13:238–252CrossRefGoogle Scholar
  8. Barz M, Luxenhofer R, Zentelb R, Vicent MJ (2011) Overcoming the PEG-addition: well-defined alternatives to PEF, from structure-property relationships to better defined therapeutics. Polym Chem 2:1900–1918CrossRefGoogle Scholar
  9. Burchard W (1983) Static and dynamic light scattering from branched polymers and biopolymers. Adv Polym Sci 48:1–124CrossRefGoogle Scholar
  10. Canelas DA, Herlihy KP, DeSimone JM (2009) Top-down particle fabrication: control of size and shape for diagnostic imaging and drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 1(4):393–404CrossRefGoogle Scholar
  11. Champion JA, Katare YK, Mitragotri S (2007) Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers. J Control Release 121:3–9CrossRefGoogle Scholar
  12. Dasa AK, Hong PD (2011) Solute–solvent friction kernels and solution properties of methyl oxazoline–phenyl oxazoline (MeOx–PhOx) copolymers in binary ethanol–water mixtures. Phys Chem Chem Phys 13:11892–11904CrossRefGoogle Scholar
  13. Derjaguin BV, Landau LD (1941) Theory of the stability of strongly charged lyophobic sols and of adhesion of strongly charged particles in solution of electrolytes. Acta Physicochim URRS 14:633–662Google Scholar
  14. Dokoumetzidis A, Macheras P (2011) The changing face of the rate concept in biopharmaceutical sciences: from classical to fractal and finally to fractional. Pharm Res 28:1229–1232CrossRefGoogle Scholar
  15. Gardikis K, Tsimplouli C, Dimas K, Micha-Screttas M, Demetzos C (2010) New chimeric advanced drug delivery nano system (chi-aDDnSs) as doxorubicin carriers. Int J Pharm 402:231–237CrossRefGoogle Scholar
  16. Gregoriadis G, Wills EJ, Swain CP, Tavill AS (1974) Drug-carrier potential of liposomes in cancer chemotherapy. Lancet 1:1313–1316CrossRefGoogle Scholar
  17. Hoogenboom R (2009) Poly(2-oxazoline)s: a polymer class with numerous potential applications. Angew Chem Int Ed Engl 48(43):7978–7994CrossRefGoogle Scholar
  18. Hoogenboom R, Wiesbrock F, Leenen MA, Meier MA, Schubert US (2005) Accelerating the living polymerization of 2-nonyl-2-oxazoline by implementing o microwave synthesizer into a high-throughput experimentation workflow. J Comb Chem 7(1):10–13CrossRefGoogle Scholar
  19. Hoogenboom R, Thijs HML, Fijten MWM, van Lankvelt B, Schubert US (2007) One-pot synthesis of 2-phenyl-2-oxazoline containing quasi diblock copoly(2-oxazoline)s under microwave irradiation. J Polym Sci A 45:416–422CrossRefGoogle Scholar
  20. Hoogenboom R, Thijs HML, Wouters D, Hoeppenera S, Schubert US (2008a) Tuning solution polymer properties by binary water–ethanol solvent mixtures. Soft Matter 4:103–107CrossRefGoogle Scholar
  21. Hoogenboom R, Thijs HML, Wouters D, Hoeppener S, Schubert US (2008b) Solvent responsive micelles based on block and gradient copoly(2-oxazoline)s. Macromolecules 41(5):1581–1583CrossRefGoogle Scholar
  22. Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 1(3):297–315CrossRefGoogle Scholar
  23. Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, Kiwada H (2006) Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of second dose of PEGylated liposomes. J Control Release 112(1):15–25CrossRefGoogle Scholar
  24. Kanniah V, Wu P, Mandzy Grulke EA (2012) Fractal analysis as a complimentary technique for characterizing nanoparticle size distributions. Powder Technol 226:189–198CrossRefGoogle Scholar
  25. Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y (1993) Block-copolymer micelles as vesicles for drug delivery. J Control Release 24:119–132CrossRefGoogle Scholar
  26. Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev 47(1):113–131CrossRefGoogle Scholar
  27. Kempe K, Lobert M, Hoogenboom R, Schubert US (2009) Synthesis and characterization a series of diverse poly(2-oxazoline)s. J Polym Sci A 47(15):3829–3838CrossRefGoogle Scholar
  28. Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl 49:6288–6308CrossRefGoogle Scholar
  29. Kono K (2001) Thermosensitive polymer-modified liposomes. Adv Drug Deliv Rev 53:307–319CrossRefGoogle Scholar
  30. Kono K, Nakai R, Morimoto K, Takagishi T (1999a) Thermosensitive polymer-modified liposomes that release contents around physiological temperature. Biochim Biophys Acta 1416:239–250CrossRefGoogle Scholar
  31. Kono K, Henmi A, Yamashita H, Hayashi H, Takagishi T (1999b) Improvement of temperature-sensitivity of poly(N-isopropylacrylamide)-modified liposomes. J Control Release 59:63–75CrossRefGoogle Scholar
  32. Lambermont-Thijs HML, Heuts JPA, Hoeppener S, Hoogenboom R, Schubert US (2011) Selective partial hydrolysis of amphiphilic copoly(2-oxazoline)s as basis for temperature and pH responsive micelles. Polym Chem 2:313–322CrossRefGoogle Scholar
  33. Lattuada M, Wu H, Morbidelli M (2003a) A simple model for the structure of fractal aggregates. J Colloid Interface Sci 268(1):106–120CrossRefGoogle Scholar
  34. Lattuada M, Sandkühler P, Wu H, Sefcik J, Morbidelli M (2003b) Aggregation kinetics of polymer colloids in reaction limited regime: experiments and simulations. Adv Colloid Interface Sci 103(1):33–56CrossRefGoogle Scholar
  35. Liu Y, Tan J, Thomas A, Ou-Yang D, Muzykantov VR (2012) The shape of things to come: importance of design in nanotechnology for drug delivery. Ther Deliv 2:181–194CrossRefGoogle Scholar
  36. Longmire MR, Ogawa M, Choyke PL, Kobayashi H (2011) Biologically optimized nanosized molecules and particles: more than just size. Bioconjugate Chem 22(6):993–1000CrossRefGoogle Scholar
  37. Lúcio M, Bringezu F, Reis S, Lima JL, Brezesinski G (2008) Binding of nonsteroidal anti-inflammatory drugs to DPPC: structure and thermodynamic aspects. Langmuir 24(8):4132–4139CrossRefGoogle Scholar
  38. Luxenhofer R, Han Y, Schulz A, Tong J, He Z, Kabanov AV, Jordan R (2012) Poly(2-oxazoline)s as polymer therapeutics. Macromol Rapid Commun 33(19):1613–1631CrossRefGoogle Scholar
  39. Milonaki Y, Kaditi E, Pispas S, Demetzos C (2011) Amphiphilic gradinet copolymers of 2-methyl- and 2-phenyl-2-oxazoline: self-organization in aqueous media and drug encapsulation. J Polym Sci A 50(2011):1226Google Scholar
  40. Mishra B, Bhavesh B, Patel Tiwari S (2010) Colloidal nanocarriers: a review on formulation technology, types and applications toward targeted drug delivery. Nanomedecine 6:9–24CrossRefGoogle Scholar
  41. Moghimi SM, Szebeni J (2003) Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 42(6):463–478CrossRefGoogle Scholar
  42. Mufamadi MS, Pillay V, Choonara YE, Du Toit LC, GirishModi G, Naidoo D, Ndesendo VMK (2011) A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv 2011:939851–939870CrossRefGoogle Scholar
  43. New RRC (1990) Liposomes a practical approach. IRL/Oxford University Press, OxfordGoogle Scholar
  44. Nunes C, Brezesinski G, Pereira-Leite C, Lima JL, Reis S, Lúcio M (2011) NSAIDs interactions with membranes: a biophysical approach. Langmuir 27(17):10847–10858CrossRefGoogle Scholar
  45. Owens DE, Peppas NA (2006) Opsonization, biodistribution and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307(1):93–102CrossRefGoogle Scholar
  46. Papagiannaros A, Dimas K, Papaioannou GT, Demetzos C (2005) Doxorubicin-PAMAM dendrimers complec attached to liposomes: cytotoxic studies against human cancer cell lines. Int J Pharm 302(1–2):29–38CrossRefGoogle Scholar
  47. Pereira LM (2010) Fractal pharmacokinetics. Comput Math Methods Med 11(2):161–184CrossRefGoogle Scholar
  48. Pippa N, Pispas S, Demetzos C (2012a) The fractal hologram and elucidation of the structure of liposomal carriers in aqueous and biological media. Int J Pharm 430(1–2):65–73CrossRefGoogle Scholar
  49. Pippa N, Pispas S, Demetzos C (2012b) The delineation of the morphology of charged liposomal vectors via a fractal analysis in aqueous and biological media: physicochemical and self-assembly studies. Int J Pharm 437(1–2):264–274CrossRefGoogle Scholar
  50. Pispas S (2011a) Self-assembled nanostructures in mixed anionic-neutral double hydrophilic block copolymer/cationic vesicle–forming surfactant solutions. Soft Matter 7:474–482CrossRefGoogle Scholar
  51. Pispas S (2011b) Vesicular structures in mixed block copolymer/surfactant solutions. Soft Matter 7:8697–8701CrossRefGoogle Scholar
  52. Pispas S, Sarantopoulou E (2007) Self-assembly in mixed aqueous solutions of amphiphilic block copolymers and vesicle-forming surfactant. Langmuir 23:7484–7490CrossRefGoogle Scholar
  53. Roldán-Vargas S, Barnabas-Rodrígez R, Martín-Molina A, Quesada-Pérez M, Estelrich J, Callejas-Fernández J (2008) Growth of lipid vesicle structures: from surface fractals to mass fractals. Phys Rev E 78:010902CrossRefGoogle Scholar
  54. Roldán-Vargas S, Barnabas-Rodrígez R, Quesada-Pérez M, Estelrich J, Callejas-Fernández J (2009) Surface fractals in liposome aggregation. The American physical society. Phys Rev 79:1–14Google Scholar
  55. Rösler A, Vandermeulen GW, Klock HA (2001) Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Adv Drug Deliv 53(1):95–108CrossRefGoogle Scholar
  56. Sabín J, Prieto G, Ruso JM, Sarmiento F (2007a) Fractal aggregates induced by liposome- liposome interaction in the presence of Ca2+. Eur Phys J E 24:201–210CrossRefGoogle Scholar
  57. Sabín J, Prieto G, Ruso JM, Messina PV, Sarmiento F (2007b) Aggregation of liposomes in presence of La3+: a study of the fractal dimension. Phys Rev E 76(011408):1–7Google Scholar
  58. Schlaad H, Diehl C, Gress A, Meyer M, Demirel AL, Nur Y, Bertin (2010) Poly(2-oxazoline)s as smart bioinspired polymers. Macromol Rapid Commun 31(6):511–521CrossRefGoogle Scholar
  59. Sedlacek O, Monnery BD, Filippov SK, Hoogenboom R, Hruby M (2012) Poly(2-oxazoline)s–are they more advantageous for biomedical applications than other polymers? Macromol Rapid Commun 33(19):1648–1662CrossRefGoogle Scholar
  60. Shimanouchi T, Sasaki M, Hiroiwa A, Yoshimoto N, Miyagawa K, Umakoshim H, Kuboi R (2011) Relationship between the mobility of phosphocholine headgroups of liposomes and the hydrophobicity at the membrane interface: a characterization with spectrophotometric measurements. Colloids Surf B 88:221–230CrossRefGoogle Scholar
  61. Sugihara H, Yamamoto H, Kawashima Y, Takeuchi H (2012) Effectiveness of submicronized chitosan-coated liposomes in oral absorption of indomethacin. J Liposome Res 22(1):72–79CrossRefGoogle Scholar
  62. Taubert A, Napoli A, Meier W (2004) Self-assembly of reactive amphiphilic block copolymers as mimetics for biological membranes. Cur Opin Chem Biol 8(6):598–603CrossRefGoogle Scholar
  63. Vial F, Tribet C (2008) Flexible macromolecules attached to lipid blayers: impact on fluidity, curvature, permeability and stability of the membranes. Soft Matter 4:68–81CrossRefGoogle Scholar
  64. Woodle MC, Engbers CM, Zalipsky S (1994) New amphipatic polymer-lipid conjugates forming long-circulating reticuloendthelial system-evading liposomes. Bioconjugate Chem 5(6):493–496CrossRefGoogle Scholar
  65. Xiong XB, Falamarzian A, Garg SM, Lavasanifar A (2011) Engineering of amphiphilic block copolymers for polymeric micellar drug and gene delivery. J Control Release 155(2):248–261CrossRefGoogle Scholar
  66. Zalipsky S, Hansen CM, Oaks JM, Allen TM (1996) Evaluation of blood clearance and biodistribution of poly(2-oxazoline)-grafted liposomes. J Pharm Sci 85(2):133–137CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Natassa Pippa
    • 1
    • 2
  • Eleni Kaditi
    • 2
  • Stergios Pispas
    • 2
  • Costas Demetzos
    • 1
  1. 1.Department of Pharmaceutical TechnologyFaculty of Pharmacy, National and Kapodistrian University of AthensAthensGreece
  2. 2.Theoretical and Physical Chemistry Institute, National Hellenic Research FoundationAthensGreece

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