Pharmaceutical Research

, Volume 18, Issue 11, pp 1613–1619 | Cite as

Influence of Surface-Modifying Surfactants on the Pharmacokinetic Behavior of 14C-Poly (Methylmethacrylate) Nanoparticles in Experimental Tumor Models

  • Jörg Lode
  • Iduna Fichtner
  • Jörg Kreuter
  • Antje Berndt
  • Julia Eva Diederichs
  • Regina Reszka


Purpose. The aim of this study was to investigate the different pharmacokinetic behavior of surface-modified poly(methylmethacrylate) (PMMA) nanoparticles.

Methods. The particles were 14C-labeled and coated with polysorbate 80, poloxamer 407, and poloxamine 908. Plain particles served as control particles. In vivo studies were performed in three tumor models differing in growth, localization, and origin. Particle suspensions were administered via the tail vein, and at given time animals were killed and organs were dissected for determination of PMMA concentration.

Results. For the PMMA nanoparticles coated with poloxamer 407 or poloxamine 908, high and long-lasting concentrations were observed in the melanoma and at a lower level in the breast cancer model. In an intracerebrally growing glioma xenograft, the lowest concentrations that did not differ between the tumor-loaded and tumor-free hemispheres were measured. Organ distribution of the four investigated batches differed significantly. For instance, poloxamer 407- and poloxamine 908-coated particles circulated over a longer period of time in the blood, leading additionally to a higher tumor accumulation. In contrast, plain and polysorbate 80-coated particles accumulated mainly in the liver. The strong expression of vascular endothelial growth factor and Flk-1 in the melanoma correlated with high concentrations of PMMA in this tumor.

Conclusion. The degree of accumulation of PMMA nanoparticles in tumors depended on the particle surface properties and the specific growth differences of tumors.

poly(methylmethacrylate) (PMMA) nanoparticles surface modification surfactant in vivo pharmacokinetics angiogenesis enhanced permeability and retention effect (EPR) tumor model 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 6:6387-6392 (1986).Google Scholar
  2. 2.
    H. Maeda and Y. Matsumura. Tumoritropic and lymphotropic principles of macromolecular drugs. CRC Crit. Rev. Ther. Drug Carrier Syst. 6:193-210 (1989).Google Scholar
  3. 3.
    L. W. Seymour. Passive tumour targeting of soluble macromolecules and drug conjugates. CRC Crit. Rev. Ther. Drug Carrier Syst. 9:135-187 (1992).Google Scholar
  4. 4.
    R. Duncan, S. Dimitijevic, and E. G. Evagorou. The role of polymer conjugates in the diagnosis and treatment of cancer. S.T.P. Pharma Sci. 6:237-263 (1996).Google Scholar
  5. 5.
    R. K. Jain. Delivery of molecular and cellular medicine to solid tumors. Microcirculation 4:1-23 (1997).Google Scholar
  6. 6.
    P. Beck, J. Kreuter, R. Reszka, and I. Fichtner. Influence of polybutylcyanoacrylate nanoparticles and liposomes on the efficacy and toxicity of the anticancer drug mitoxantrone in murine tumor models. J. Microencapsul. 10:101-114 (1993).Google Scholar
  7. 7.
    R. Reszka, P. Beck, I. Fichtner, M. Hentschel, J. Richter, and J. Kreuter. Body distribution of free, liposomal and nanoparticle-associated mitoxantrone in B16-Melanoma-bearing mice. J. Pharmacol. Exp. Ther. 280:232-237 (1997).Google Scholar
  8. 8.
    S. D. Tröster, K. H. Wallis, R. H. Müller, and J. Kreuter. Correlation of the surface hydrophobicity of 14C-poly(methyl methacrylate) nanoparticles to their body distribution. J. Control. Release 20:247-260 (1992).Google Scholar
  9. 9.
    S. D. Tröster and J. Kreuter. Influence of the surface properties of low contact angle surfactants on the body distribution of 14C-poly(methyl methacrylate) nanoparticles. J. Microencapsulation 9:19-28 (1992).Google Scholar
  10. 10.
    U. Schröder and B. A. Sabel. Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections. Brain Res. 710:121-124 (1996).Google Scholar
  11. 11.
    J. Kreuter, R. N. Alyautdin, D. A. Kharkevich, and A. A. Ivanov. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res. 674:171-174 (1995).Google Scholar
  12. 12.
    R. N. Alyautdin, D. Gothier, V. E. Petrov, D. A. Kharkevich, and J. Kreuter. Analgesic activity of the hexapeptide dalargin adsorbed on the surface of polysorbate 80-coated poly(butylcyanoacrylate) nanoparticles. Eur. J. Pharm. Biopharm. 41:44-48 (1995).Google Scholar
  13. 13.
    R. N. Alyautdin, V. E. Petrov, K. Langer, A. Berthold, D. A. Kharkevich, and J. Kreuter. Delivery of loperamid across the blood-brain barrier with polysorbate 80-coated poly-butyl-cyanoacrylate nanoparticles. J. Pharm. Res. 14:325-328 (1997).Google Scholar
  14. 14.
    J. Kreuter, U. Täuber, and V. Illi. Distribution and elimination of poly(methyl-2-14C-methacrylate) nanoparticle radioactivity after injection in rats and mice. J. Pharm. Sci. 68:1443-1447 (1979).Google Scholar
  15. 15.
    F. Brasseur, P. Couvreur, B. Kante, L. Deckers-Passau, M. Roland, C. Deckers, and P. Speiser. Actinomycin D adsorbed on polymethylmethacrylate nanoparticles: an increased efficiency against an experimental tumor. Eur. J. Cancer 16:1441-1445 (1980).Google Scholar
  16. 16.
    P. Couvreur, L. Grislain, and V. Lenaerts. Biodegradable polymeric nanoparticles as a drug carrier for antitumor agents. In P. Guiot and P. Couvreur (eds.), Polymeric Nanoparticles and Microspheres, CRC Press, Boca Raton, 1986.Google Scholar
  17. 17.
    D. Sharma, T. Chelvi, J. Kaur, K. Chakravorty, T. De, A. Maitra, and R. Ralham. Novel Taxol® formulation: polyvinylpyrolidone nanoparticle-encapsulated Taxol® for drug delivery in cancer therapy. Oncol. Res. 8:281-286 (1996).Google Scholar
  18. 18.
    E. M. Gipps, R. Arshady, J. Kreuter, P. Groscurth, and P. P. Speiser. Distribution of polyhexylcyanoacrylate nanoparticles in nude mice bearing human osteosarcoma. J. Pharm. Sci. 75:256-258 (1986).Google Scholar
  19. 19.
    B. Endrich, H. S. Reinhold, J. F. Gross, and M. Intaglietta. Tissue perfusion inhomogeneity during early tumor growth in rats. J. Natl. Cancer Inst. 62:387-395 (1979).Google Scholar
  20. 20.
    J. Kreuter. Drug targeting with nanoparticles. Eur. J. Drug Metab. Pharmacokinet. 3:253-256 (1994).Google Scholar
  21. 21.
    S. E. Dunn, A. G. A. Coombes, M. C. Garnett, S. S. Davis, M. C. Davies, and L. Illum. In vitro cell interaction and in vivo biodistribution of poly (lactide-co-glycolide) nanospheres surface modified by poloxamer and poloxamine copolymers. J. Control. Release 44:65-76 (1997).Google Scholar
  22. 22.
    J. E. O'Mullane, P. Artursson, and E. Tomlinson. Biopharmaceutics of microparticle drug carriers. Ann. NY Acad. Sci. 507:100-140 (1987).Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Jörg Lode
    • 1
  • Iduna Fichtner
    • 1
  • Jörg Kreuter
    • 2
  • Antje Berndt
    • 1
  • Julia Eva Diederichs
    • 1
  • Regina Reszka
    • 1
  1. 1.Max-Delbrück-Center for Molecular MedicineBerlinGermany
  2. 2.Institute of Pharmaceutical TechnologyJ. W. Goethe-Universität, BiozentrumFrankfurt/Main

Personalised recommendations