Molecular and Cellular Biochemistry

, Volume 120, Issue 2, pp 119–126 | Cite as

Influence of liposome charge and composition on their interaction with human blood serum proteins

  • Trinidad Hernández-Caselles
  • José Villalaín
  • Juan C. Gómez-Fernández


Lipid composition and specially their electrostatic properties, were found to greatly influence the stability of liposomes in human blood serum. The amount and type of serum proteins bound to the liposomes were also clearly influenced by lipid composition and charge of liposomes. a good correlation was found between the amount of serum proteins adsorbed to a given type of liposome and its instability as measured by the release of an encapsulated fluorescent probe. Liposomes that bind the highest amount of protein were the least stable, except for the case of liposomes containing gangliosides, which were fairly stable even at a high amount of bound protein. Liposomes with neutral charge containing phosphatidylcholine were the most stable and bound the lowest amount of protein. Liposomes with positive charge behaved similarly to those with neutral charge. However, the stability of negatively charged liposomes was very dependent on their composition. Those liposomes containing only one class of negatively charged phospholipids bound a great amount of protein and were very unstable. However, those liposomes containing also phosphatidylcholine bound less protein and were more stable. The examination of the electrophoresis patterns of serum proteins bound to the different types of liposomes indicated the presence of specific proteins which correlated with liposome instability. (Mol Cell Biochem120: 119–126, 1993)

Key Words

liposome stability liposome-blood interaction 























Reticuloendothelial system






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  1. 1.
    Gregoriadis G: Targeting of drugs. Nature 265: 407–411, 1977Google Scholar
  2. 2.
    Juliano RL, Stamp D: Pharmacokinetics of liposome encapsulated anti-tumor drugs. Biochem Pharmacol 27: 21–27, 1978Google Scholar
  3. 3.
    Juliano RL: Renaissance of the magic bullet: an essay on the controlled delivery of drugs. Pharmacy Int 2: 41–45, 1980Google Scholar
  4. 4.
    Scherphof GI, Damen J, Wilschut J: Interactions of liposomes with plasma proteins. In: Gregoriadis G (ed) Liposome Technology. CRC Press, Boca Ratón, Florida, Vol 3, 1984, pp 205–224Google Scholar
  5. 5.
    Senior J, Gregoriadis G: Methodology in assessing liposomal stability in the presence of blood, clearance from the circulation of injected animals, and uptake by tissues. In: Gregoriadis G (ed) Liposome Technology. CRC Press, Boca Ratón, Florida, Vol 3, 1984, pp 263–282Google Scholar
  6. 6.
    Juliano RL: Interaction of proteins and drugs with liposomes. In: Ostro MJ (ed) Liposomes. Marcel Dekker, New York, 1983, pp 53–86Google Scholar
  7. 7.
    Bonte F, Juliano RL: Interaction of liposomes with serum proteins. Chem Phys Lipids 40: 359–372, 1986Google Scholar
  8. 8.
    Black CDV, Gregoriadis G: Interaction of liposomes with blood plasma proteins. Biochem Soc Trans 4: 253–256, 1976Google Scholar
  9. 9.
    Kirby C, Gregoriadis G: The effect of the cholesterol content of small unilamellar liposomes on the fate of their lipid componentsin vivo. Life Sci 22: 2223–2230, 1980Google Scholar
  10. 10.
    Allen TM, Ryan JL, Papahadjopoulos D: Gangliosides reduce leakage of aqueous-space markers from liposomes in the presence of human plasma. Biochim Biophys Acta 818: 205–210, 1985Google Scholar
  11. 11.
    Allen TM, Hansen C, Rutledge J: Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta 981: 27–35, 1989Google Scholar
  12. 12.
    Agarwal K, Bali A, Gupta CM: Effect of phoepholipid structure on stability and survival times of liposomes in circulation. Biochim Biophys Acta 883: 468–475, 1986Google Scholar
  13. 13.
    Bonté F, Hsu MJ, Papp A, Wu K, Regen SL, Juliano RL: Interactions of polymerizable phosphatidylcholine vesicles with blood components: relevance to biocompatibility. Biochim Biophys Acta 900: 1–9, 1987Google Scholar
  14. 14.
    Juliano RL, Lin G: The interaction of plasma proteins with liposomes: protein binding and effects of the clotting and complement systems. In: Tom BH, Six HR (eds.) Liposomes and Immunology. Elsevier, Amsterdam. pp 49–66, 1980Google Scholar
  15. 15.
    Moghimi SM, Patel HM: Tissue specific opsonins for phagocytic cells and their different affinity for cholesterol rich liposomes. FEBS Letters 233: 143–147, 1988Google Scholar
  16. 16.
    Scherphof G, Roerdink F, Waite M, Parks J: Disintegration of phosphatidylcholine liposomes in plasma as a result of interactions with high density lipoproteins. Biochim Biophys Acta 542: 296–307, 1978Google Scholar
  17. 17.
    Moghimi SM, Patel HM: Different properties of organ-specific serum opsonins for liver and spleen macrophages. Biochim Biophys Acta 984: 379–383, 1989Google Scholar
  18. 18.
    Altman PL, Dittman DS: Blood and other Body fluids. Fed Am Soc Exp Biol, Washington DC, 1961Google Scholar
  19. 19.
    Ralston E, Hjelmeland LM, Klausner RD, Weinstein JN, Blumenthal R: Carboxyfluorescein as a probe for liposome-cell interactions. Effects of impurities and purification of the dye. Biochim Biophys Acta 649: 133–137, 1981Google Scholar
  20. 20.
    Bartlett GR: Phosphorus assay in column chromatography. J Biol Chem 234: 466–471, 1958Google Scholar
  21. 21.
    Lowry OK, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275, 1951Google Scholar
  22. 22.
    Wang C-S, Smith RL: Lowry determination of protein in the presence of Triton X-100. Anal Biochem 63: 414–417, 1975Google Scholar
  23. 23.
    Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970Google Scholar
  24. 24.
    Weber K, Osborn M: The reliability of molecular weight determinations by dodecyl sulfate polyacrylamide gel electrophoresis. J Biol Chem 244: 4406–4419, 1969Google Scholar
  25. 25.
    Marsh D: Handbook of Lipid Bilayers, CRC Press, Boca Ratón, Florida, 1990Google Scholar
  26. 26.
    Allen TM, Chonn A: Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Letters 1: 42–46, 1987Google Scholar
  27. 27.
    Boggs JM: Intermolecular hydrogen bonding between membrane lipids. In: Kates M, Manson LA (eds) Membrane fluidity. Plenum Publishing Corp, New York, 1984, pp 3–53Google Scholar
  28. 28.
    Kirby C, Clarke J, Gregoriadis G: Effect of the cholesterol content of small unilamellar liposomes on their stabilityin vivo andin vitro. Biochem J 186: 591–598, 1980Google Scholar
  29. 29.
    Oldfield E, Chapman D: Dynamics of lipids in membranes. Heterogeneity and the role of cholesterol. FEBS Letters 23: 285–297, 1972Google Scholar
  30. 30.
    Kirby C, Clarke J, Gregoriadis G: Cholesterol content of small unilamellar liposomes controls phospholipid loss to high density lipoproteins in the presence of serum. FEBS Letters 111: 324–328, 1980Google Scholar
  31. 31.
    Gabizon A, Papahadjopoulos D: Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85: 6949–6953, 1988Google Scholar
  32. 32.
    Van Rooijen N, Van Nieuwmegen R: Liposomes in immunology: multilamellar phosphatidylcholine liposomes as a simple, biodegradable and harmless adjuvant without any immunologic activity of its own. Cell Immunol 49: 402–407, 1980Google Scholar
  33. 33.
    Tall IJ, Lange Y: Incorporation of cholesterol into high density lipoprotein recombinants. Biochem Biophys Res Comm 80: 206–212, 1978Google Scholar
  34. 34.
    Op den Kamp JAF, Kauerz MT, Van Deenen LLM: Action of pancreatic phospholipase A2. Biochim Biophys Acta 406: 169–177, 1975Google Scholar
  35. 35.
    Patel HM, Tuzel NS, Ryman BE: Inhibitory effect of cholesterol on the uptake of liposomes by liver and spleen. Biochim Biophys Acta 761: 142–151, 1983Google Scholar
  36. 36.
    Bing DH, Rosenbaum RA: Plasma and cellular modulatory proteins, Center for Blood Research, Boston, 1981Google Scholar
  37. 37.
    Malamud D, Drysdale JW: Isoelectric points of proteins: A Table. Anal Biochem 86: 620–647, 1978Google Scholar
  38. 38.
    Hsu MJ, Juliano RL: Interaction of liposomes with the reticuloendothelial systems. II. Non-specific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages. Biochim Biophys Acta 720: 411–419, 1982Google Scholar
  39. 39.
    Allen TM, Williamson P, Schlegel RA: Phosphatydylserine as a determinant of reticuloendothelial recognition of liposome models of the erythrocyte surface. Proc Natl Acad Sci USA 85: 8067–8072, 1988Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Trinidad Hernández-Caselles
    • 1
  • José Villalaín
    • 1
  • Juan C. Gómez-Fernández
    • 1
  1. 1.Departamento de Bioquímica y Biología Molecular A, Facultad de VeterinariaUniversidad de MurciaMurciaSpain

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