Interactions of Liposomes with Lipoproteins and Liver Cells In Vivo and In Vitro Studies

  • Gerrit Scherphof
  • Jan Damen
  • Jan Dijkstra
  • Frits Roerdink
  • Halbe Spanjer


Detailed knowledge on the in-vivo behaviour of liposomes and of the factors influencing such behaviour is a necessity for any serious attempt to apply liposomes as an in-vivo carrier system for both therapeutics and diagnostics. For several years now our group has made an effort to study liposomes in-vivo and, in doing so, we have paid special attention to the interaction with blood components such as lipoproteins and to the role of the liver and its various cell populations in the elimination of liposomes from the bloodstream and their subsequent processing.


Parenchymal Cell Kupffer Cell Small Unilamellar Vesicle Lipid Label Liposomal Phospholipid 
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.
    G. Scherphof, F. Roerdink, D. Hoekstra, J. Zborowski and E. Wisse, Stability of liposomes in presence of blood constituents: consequences for uptake of liposomal lipid and entrapped compounds by rat-liver cells, in “Liposomes in Biological Systems” G. Gregoriadis and A.C. Allison, eds., John Wiley, Chichester. (1980).Google Scholar
  2. 2.
    G. Scherphof, F. Roerdink, J. Dijkstra, H. Ellens, R. de Zanger and E. Wisse, Uptake of liposomes by rat and mouse hepatocytes and Kupffer cells, Biol. Cell. 47:47 (1983).Google Scholar
  3. 3.
    F. Roerdink, J. Dijkstra, G. Hartman, B. Bolscher and G. Scherphof, The involvement of parenchymal, Kupffer and endothelial liver cells in hepatic uptake of intravenously injected liposomes. Effects of lanthanum and gadolinium salts, Biochim. Biophys. Acta. 677:79 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    F.H. Roerdink, E. Wisse, H.W.M. Morselt, J. van Meulen and G.L. Scherphof, Cellular distribution of intravenously injected protein-containing liposomes in the rat liver, in “Kupffer cells and other liver sinusoidal cells” E. Wisse and D. Knook, eds., Elsevier/North-Holland, Amsterdam. (1977).Google Scholar
  5. 5.
    H. Ellens, H.W.M. Morselt, B.H.J. Donje, D. Kalicharan, C.E. Hulstaert and G.L. Scherphof, Effects of liposome dose and the presence of lymphosarcoma cells on blood clearance and tissue distribution of large unilamellar liposomes in mice, Cancer Res., 43:2927 (1983).PubMedGoogle Scholar
  6. 6.
    J. van Renswoude and D. Hoekstra, Cell-induced leakage of liposome contents, Biochemistry. 20:540. (1981).PubMedCrossRefGoogle Scholar
  7. 7.
    R. Fraley, R.M. Straubinger, G. Rule, E.L. Springer and D. Papahadjopoulos, Liposome-mediated delivery of deoxyribonucleic-acid to cells: Enhanced efficiency of delivery related to lipid composition and incubation conditions, Biochemistry.20:6978 (1981).PubMedCrossRefGoogle Scholar
  8. 8.
    L. Krupp, A.V. Chobanian and P.I. Brecher, The in-vivo transformation of phospholipid vesicles to a particle resembling HDL in the rat, Biochem. Biophys. Res. Commun., 72.1251 (1976).PubMedCrossRefGoogle Scholar
  9. 9.
    G. Scherphof, F. Roerdink, M. Waite, and J. Parks, Disintegration of phosphatidylcholine liposomes as a result of interaction with high-density lipoproteins, Biochim. Biophys. Acta, 542:296 (1978).PubMedCrossRefGoogle Scholar
  10. 10.
    A.R. Tall and D.M. Small, Solubilisation of phospholipid membranes by human plasma high-density lipoproteins, Nature. 265:163 (1977).PubMedCrossRefGoogle Scholar
  11. 11.
    M.C. Finkelstein and G. Weissmann, Enzyme replacement via liposomes; variations in lipid composition determine liposomal integrity in biological fluids, Biochim. Biophys. Acta 587:202 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    C. Kirby, J. Clarke and G. Gregoriadis, Effect of the cholesterol content of small unilamellar liposomes on their stability in vivo and in vitro, Biochem. J. 186:591 (1980).PubMedGoogle Scholar
  13. 13.
    T.M. Allen and L.G. Cleland, Serum-induced leakage of liposome contents, Biochim. Biophys. Acta. 597:418 (1980).PubMedCrossRefGoogle Scholar
  14. 14.
    J. Damen, J. Dijkstra, J. Regts and G. Scherphof, Effect of lipoprotein-free plasma on the interaction of human plasma high density lipoprotein with egg yolk phosphatidylcholine liposomes, Biochim. Biophys. Acta.620:90 (1980).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Damen, J. Regts and G. Scherphof, Transfer and exchange of phospholipid between small unilamellar liposomes and rat plasma high density lipoproteins: dependence on cholesterol and phospholipid composition, Biochim. Biophys. Acta. 665:538 (1981).PubMedCrossRefGoogle Scholar
  16. 16.
    G. Scherphof, B. van Leeuwen, J. Wilschut and J. Damen, Exchange of phosphatidylcholine between small unilamellar liposomes and human high density lipoprotein exclusively involves the phospholipid in the outer monolayer of the liposomal membrane, Biochim. Biophys. Acta. 732:595 (1983).PubMedCrossRefGoogle Scholar
  17. 17.
    J.C. Wilschut, J. Regts and G. Scherphof, Action of phosolipase A2 on phospholipid vesicles: Preservation of the membrane permeability barrier during asymmetric bilayer degradation, FEBS Lett. 98:181 (1979).PubMedCrossRefGoogle Scholar
  18. 18.
    J.C. Wilschut, Preparation and properties of phospholipid vesicles, in “Liposome Methodology”, D. Leserman and J. Barbet, eds., Inserm, Paris, (1982).Google Scholar
  19. 19.
    G.L. Scherphof, J. Damen and J. Wilschut, Interactions of liposomes with plasma proteins in “Liposome Technology”, G. Gregoriadis, ed., CRC Press, Boca Raton (1984).Google Scholar
  20. 20.
    C. Kirby and G. Gregoriadis, Plasma-induced release of solutes from small unilamellar liposomes is associated with pore formation in the bilayers, Biochem J. 199:251 (1981).PubMedGoogle Scholar
  21. 21.
    J.C. Wilschut, J. Regts, H. Westenberg and G. Scherphof, Action of phospholipases A2 on phosphatidylcholine bilayers. Effect of the phase transition, bilayer curvature and structural defects, Biochim. Biophys. Acta.508; 185 (1978).PubMedCrossRefGoogle Scholar
  22. 22.
    J. Damen, J. Regts and G. Scherphof, Transfer of 14C phosphatidylcholine between liposomes and human plasma high density lipoprotein: partial purification of a transfer stimulating plasma factor using a rapid transfer assay, Biochim. Biophys. Acta. 712:444 (1982).PubMedCrossRefGoogle Scholar
  23. 23.
    A.R. Tall, L.R. Forester and G.L. Bongiovanni, Facilitation of phosphatidylcholine transfer into high density lipoproteins by an apolipoprotein in the density 1.20–1.26 g/ml fraction of plasma J. Lipid Res. 24:277 (1983).PubMedGoogle Scholar
  24. 24.
    J. Dijkstra, W.J.M. van Galen, F.H. Roerdink, D. Regts and G.L. Scherphof, Uptake of liposomes by Kupffer cells in vitro, in “Sinusoidal Liver Cells”, D.L. Knook and E. Wisse, eds., Elsevier Biomedical Press, Amsterdam, (1982).Google Scholar
  25. 25.
    J. Dijkstra, W.J.M. van Galen, C.E. Hulstaert, D. Kalicharan, F.H. Roerdink and G.L. Scherphof, Interaction of liposomes with Kupffer cells in vitro, Exp. Cell Res. 150:161 (1984).PubMedCrossRefGoogle Scholar
  26. 26.
    D.J. Reijngoud, P.S. Oud, J. Kas and J.M. Tager, Relationship between medium pH and that of the lysosomal matrix as studied by two independent methods, Biochim Biophys. Acta. 448:290 (1976).PubMedCrossRefGoogle Scholar
  27. 27.
    S. Ohkuma and B. Poole, Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents, Proc. Natl. Acad. Sci. USA, 75:3327 (1978).PubMedCrossRefGoogle Scholar
  28. 28.
    P.O. Seglen, B. Grinde and A.E. Solheim, Inhibition of the lysosomal pathway of protein degradation in isolated rat hepa-tocytes by ammonia, methylamine, chloroquine and leupeptin, Eur. J. Biochem. 95:215 (1979).PubMedCrossRefGoogle Scholar
  29. 29.
    R.L. Juliano and D. Stamp, The effect of particle size and charge on the clearance rates of liposomes and liposome encapsulated drugs, Biochem Biophys. Res. Commum. 63:651 (1975).CrossRefGoogle Scholar
  30. 30.
    G.H. Hinkle, G.S. Born, W.V. Kessler and S.M. Shaw, Preferential localization of radiolabeled liposomes in liver, J. Pharm. Sci. 67:795 (1978).PubMedCrossRefGoogle Scholar
  31. 31.
    E. Wisse, An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids, J. Ultrastruct. 31:125 (1970).CrossRefGoogle Scholar
  32. 32.
    G. Ashwell and A.G. Moreli, The role of surface carbohydrates in the hepatic recognition and transport of circulating glycoproteins, Adv. Enzymol. 41:99 (1974).PubMedGoogle Scholar
  33. 33.
    G. Gregoriadis and D.E. Neerunjun, Control of the fate of hepatic uptake and catabolism of liposome-entrapped proteins injected into rats. Possible therapeutic applications, Eur. J. Biochem. 47:179 (1974).PubMedCrossRefGoogle Scholar
  34. 34.
    L.D. Steger and R.J. Desnick, Enzyme therapy VI. Comparative in-vivo fates and effects on lysosomal integrity of enzyme entrapped in negatively and positively charged liposomes, Biochim. Biophys. Acta. 464:530 (1977).PubMedCrossRefGoogle Scholar
  35. 35.
    G. Gregoriadis and D.E. Neerunjun, Homing of liposomes to target cells, Biochem. Biophys. Res. Commun. 65:537 (1975).CrossRefGoogle Scholar
  36. 36.
    P. Ghosh and B.K. Bachhawat, Grafting of different glycosides on the surface of liposomes and its effect on the tissue distribution of 125I-labeled γ-globulin encapsulated in liposomes, Biochim. Biophys. Acta. 632:562 (1980).PubMedCrossRefGoogle Scholar
  37. 37.
    P. Ghosh, P.K. Das and B.K. Bachhawat, Targeting of liposomes towards different cell types of rat liver through the involvement of liposomal surface glycosides, Arch. Biochem. Biophys. 213:266 (1982).PubMedCrossRefGoogle Scholar
  38. 38.
    F.C. Szoka and E. Mayhew, Alteration of liposome disposition in-vivo by bilayer situated carbohydrates, Biochem. Biophys. Res. Commun. 110:140 (1983).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Spanjer and G. Scherphof, Targeting of lactosylceramide containing liposomes to hepatocytes in-vivo, Biochim. Biophys. Acta. 734:40 (1983).PubMedCrossRefGoogle Scholar
  40. 40.
    V. Kolb-Bachofen, J. Schlepper-Schäffer, W. Vogell and H. Kolb, Electron microscopic evidence for an asialoglycoprotein receptor on Kupffer cells: localization of lectin-mediated endocy-tosis, Cell. 29:859 (1982).PubMedCrossRefGoogle Scholar
  41. 41.
    E. Muller, M.W. Franco and R. Schauer, Involvement of membrane galactose in the in-vivo and in-vitro sequestration of desialylated erythrocytes, Hoppe Seyler’s Z. Physiol. Chem.362:1615. (1981).PubMedCrossRefGoogle Scholar
  42. 42.
    E. Wisse, R. de Zanger and R. Jacobs, Lobular gradients in endothelial fenestrations and sinusoidal diameter favor centro-lubular exchnage processes: a scanning EM study in “Sinusoidal Liver Cells” D.L. Knook and E. Wisse, eds., Elsevier Biomedical Press, Amsterdam, (1982).Google Scholar
  43. 43.
    M.R. Mauk, R.C. Gamble and J.D. Baldeschwieler, Vesicle targeting: timed release and specificity for leukocytes in mice by subcutaneous injection, Science 207:309 (1980).PubMedCrossRefGoogle Scholar
  44. 44.
    G. Gregoriadis, C. Kirby, P. Large, A. Meehan and J. Senior, Targeting of liposomes: study of influencing factors, in “Targeting of Drugs”, G. Gregoriadis, J. Senior and A. Trouet, eds., Plenum, New York, (1982).CrossRefGoogle Scholar
  45. 45.
    D. Hoekstra, R. Tomasini and G. Scherphof, Interaction of phospholipid vesicles with rat hepatocytes in primary monolayer culture, Biochim. Biophys. Acta. 542:456 (1978).PubMedCrossRefGoogle Scholar
  46. 46.
    D. Hoekstra, and G. Scherphof, Effect of foetal calf serum and serum protein fractions on the uptake of liposomal phosphatidylcholine by rat hepatocytes in primary monolayer culture, Biochim. Biophys. Acta. 551:109 (1979).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Gerrit Scherphof
    • 1
  • Jan Damen
    • 2
  • Jan Dijkstra
    • 3
  • Frits Roerdink
    • 1
  • Halbe Spanjer
    • 1
  1. 1.Laboratory of Physiological ChemistryUniversity of GroningenGroningenThe Netherlands
  2. 2.Division of Cell BiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of Pharmacology, School of PharmacyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations