Intravenously Injected Particles

Surface Properties and Interaction with Blood Proteins—The Key Determining the Organ Distribution
  • Rainer H. Müller
  • Martin Lück
  • Stephan Harnisch
  • Kai Thode


The knowledge and controlled exploitation of the basic mechanisms determining the organ distribution of i.v. injected particles could be used to target diagnostics and colloidal drug carriers to their desired site of action. Basic studies with indifferent model particles (polystyrene latex) have been performed and the results are, at present, being transferred to magnetite particles used in magnet resonance imaging (MRI). In earlier experiments, it was possible to explain the basic mechanisms leading to a specific organ distribution of intravenously injected particles by just considering their physicochemical properties. However, a straight correlation between physicochemical data and organ distribution could not be established. For example, 60 nm polystyrene particles surface-modified by the adsorption of two different block-copolymers differed only slightly in their physicochemical characterisation data but showed a completely different organ distribution. This led to today’s paradigm that the key factor for the in vivo behaviour of particles is the interaction of the injected particles with plasma proteins. For the analysis of plasma protein adsorption, two-dimensional electrophoresis was established and successfully applied to the analysis of diagnostic magnetic particles used in MRI. As a new approach for the site-specific enrichment of particles, the concept of “differential protein adsorption” was developed.


Surface Hydrophobicity Protein Adsorption Iron Oxide Particle Rose Bengal Polystyrene Particle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ehrlich P (1906). Collected studies on immunity. New York, John Wiley and Sons.Google Scholar
  2. 2.
    Müller RH (1991). Colloidal carriers for controlled drug delivery and targeting. Stuttgart, Wissenschaftliche Verlagsgesellschaft and Boca Raton, CRC Press.Google Scholar
  3. 3.
    Ilium L and Davis SS (1987). Targeting of colloidal drug carriers to the bone marrow. Life Sciences 40, 1553.CrossRefGoogle Scholar
  4. 4.
    Blum L, Davis SS, Müller RH, Mak E, West P (1987). The organ distribution and circulation time of intravenously injected colloidal carriers sterically stabilised with blockcopolymer - poloxamine 908. Life Sciences 40, 367.CrossRefGoogle Scholar
  5. 5.
    Tröster SD, Müller RH, Kreuter J (1990). Modification of the body distribution of poly (methyl methacrylate) nanoparticles in rats by coating with surfactants. International Journal of Pharmaceutics 61, 85.CrossRefGoogle Scholar
  6. 6.
    Alyautdin R, Gothier D, Petrov V, Kharkevich D and Kreuter J (1995). Analgesic activity of the hexapeptide Dalargin adsorbed on the surface of Polysorbate. European J. Pharmaceutics and Biopharmaceutics 1, 44–48.Google Scholar
  7. 7.
    Ehlers S, Bucke W, Leitzke S, Fortmann L, Smith D, Hänsch H, Hahn H, Bancroft G, Müller RH (1996). Liposomal amikacin for treatment of M. avium infections in clinically relevant experimental settings. International Journal of Medical Microbiology, Parasitology and Infectious Diseases 284, 218–231.Google Scholar
  8. 8.
    Wilkins DJ and Myers PA (1966). Studies on the relationship between the electrophoretic properties ofcolloids and their blood clearance and organ distribution in the rat. British Journal of Experimental Pathology 47, 568–576.Google Scholar
  9. 9.
    Yamaoka T, Tabata Y, Ikada Y (1993). Blood clearance and organ distribution of intravenously administered polystyrene microspheres of different size. Journal of Bioactive and Compatible Polymers 8, 220–235.CrossRefGoogle Scholar
  10. 10.
    Davis SS (1981). Colloids as drug-delivery systems. Pharmaceutical Technology 5, 71–88.Google Scholar
  11. 11.
    Müller RH, Rühl D, Lück M, Paulke BR (1997). Influence of fluorescent labelling of polystyrene particles on phagocytic uptake, surface hydrophobicity and plasma protein adsorption. Pharmaceutical Research, in press.Google Scholar
  12. 12.
    Tröster SD and Kreuter J (1988). Contact angle of surfactants with a potential to alter the body distribution of colloidal drug carriers on poly(methyl methacrylate) surfaces. International Journal of Pharmaceutics 45, 91–100.CrossRefGoogle Scholar
  13. 13.
    Lukowski G, Müller RH, Müller BW, Dittgen M (1992). Acrylic acid copolymer nanoparticles for drug delivery: I. Characterisation of the surface properties relevant for in vivo organ distribution. International Journal of Pharmaceutics 84, 23–31.CrossRefGoogle Scholar
  14. 14.
    Smyth CJ, Jonsson P, Olsson E, Söderlind O, Rosengren J Hjerten S, Wadström T (1978). Differences in hydrophobic surface characteristics of porcine enteropathogenic Escherichia coli with or without K88, antigen as revealed by hydrophobic interaction chromatography. Infection and Immunity. 22, 462–472.Google Scholar
  15. 15.
    Wallis KH and Müller RH (1993). Determination of the surface hydrophobicity of colloidal dispersions by Mini-Hydrophobic Interaction Chromatography. Pharm. Ind. 55, 12, 1124–1128.Google Scholar
  16. 16.
    Müller RH and Heinemann S (1989). Surface modelling of microparticles as parenteral systems with high tissue affinity. In Bioadhesion–Possibilities and Future Trends. Gurny R and Junginger HE (Eds), Stuttgart, Wissenschaftliche Verlagsgesellschaft, 202–213.Google Scholar
  17. 17.
    Juliano RL (1988). Factors affecting the clearance kinetics and tissue distribution of liposomes, micro-spheres and emulsions. Advances in Drug Delivery Reviews 2, 31–54.CrossRefGoogle Scholar
  18. 18.
    Davis SS, Ilium L, Moghimi SM, Davies MC et al (1993). Microspheres for targeting drugs to specific body sites. Journal of Controlled Release 24, 157–163.CrossRefGoogle Scholar
  19. 19.
    Blunk T (1994). Plasmaproteinadsorption aufkolloidalenArzneistoffträgern. Ph D thesis, University of Kiel.Google Scholar
  20. 20.
    Blunk T, Hochstrasser DF, Sanchez J-C, Müller BW, Müller RH (1993). Colloidal carriers for intravenous drug targeting: Plasma protein adsorption patterns on surface-modified latex particles evaluated by two-dimensional polyacrylamide gel electrophoresis. Electrophoresis 14, 1382–1387.CrossRefGoogle Scholar
  21. 21.
    Müller RH (1989). Differential adsorption for the targeting of drug carriers. Acta Pharmaceutica Technologies 36, 34S.Google Scholar
  22. 22.
    Müller RH (1989). Differential opsonisation - a new approach for the targeting of colloidal drug carriers. Archiv der Pharmazie 322, 700.Google Scholar
  23. 23.
    Porter CJH, Moghimi SM, Ilium L, Davis SS (1992). The polyoxyethylene/polyoxypropylene block copolmer poloxamer-407 selectivity redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow FEBS Letters 305, 62–67.Google Scholar
  24. 24.
    Blunk T, Lück M, Calvör A, Hochstrasser DF, Sanchez JC, Müller BW, Müller RH (1996). Kinetics of plasma protein adsorption on model particles for controlled drug delivery and drug targeting. European Journal of Pharmaceutics and Biopharmaceutics 4, 262–268.Google Scholar
  25. 25.
    Vroman L (1986). Adsorption of proteins out of plasma and solutions in narrow spaces. Journal of Colloid and Interface Sciences 111, 391–402.CrossRefGoogle Scholar
  26. 26.
    Diederichs JE (1996). Plasma protein adsorption patterns on liposomes: Establishment of analytical procedure. Electrophoresis 17, 607–611.CrossRefGoogle Scholar
  27. 27.
    Thode K (1996). Spezifische Kontrastmittel far die Magnetresonanz-Tomographie: Physikochemische Charakterisierung und Studien zur Plasmaproteinadsorption. Ph D thesis, Free University of Berlin.Google Scholar
  28. 28.
    Hochstrasser DF, Harrington MG, Hochstrasser A-C, Miller MJ and Merril CR (1988). Methods for increasing the resolution of two-dimensional protein electrophoresis. Anal. Biochem. 173, 424–435.CrossRefGoogle Scholar
  29. 29.
    Appel RD, Hochstrasser DF, Funk M, Vargas JR, Pellegrini C, Muller AF and Scherrer JR (1991). The MELANIE project: From a biopsy to automatic protein map interpretation by computer. Electrophoresis 12, 722–735.CrossRefGoogle Scholar
  30. 30.
    Anderson NL and Anderson NG (1991). A two-dimensional gel database of human plasma proteins. Electrophoresis 12, 883–906.CrossRefGoogle Scholar
  31. 31.
    Golaz O, Hughes GJ, Frutiger S, Paquet N, Bairoch A, Pasquali C, Sanchez J-C, Tissot J-D, Appel RD, Walzer C, Balant L and Hochstrasser DF (1993). Plasma and red blood cell protein maps: Update 1993. Electrophoresis 14, 1223–1231.CrossRefGoogle Scholar
  32. 32.
    Pownall HJ and Gotto Jr. AM (1992). Human plasma apolipoproteins in biology and medicine. In Structure and Function of Apolipoproteins. Rosseneu M (Ed). Boca Raton, CRC Press, Inc., 1–32.Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Rainer H. Müller
    • 1
  • Martin Lück
    • 1
  • Stephan Harnisch
    • 1
  • Kai Thode
    • 1
    • 2
  1. 1.Department of Pharmaceutics, Biopharmaceutics, and BiotechnologyThe Free University of BerlinBerlinGermany
  2. 2.Institute of Diagnostic ResearchFree University of BerlinBerlinGermany

Personalised recommendations