Long Circulating Liposomes: Evolution of the Concept

  • Gregory Gregoriadis
Part of the NATO ASI Series book series (NSSA, volume 300)


The use of liposomes as a drug-carrier, proposed and tested in the early 1970s (Gregoriadis et al., 1971; Gregoriadis and Ryman, 1972a), has undergone a multitude of stages that have recently culminated in the licencing and marketing of several injectable pharmaceutical products (Gregoriadis, 1995). Comments on the impact of liposomes on drug delivery and targeting has been made elsewhere (Gregoriadis, 1998). Here, I discuss some of the key developments which contributed to the understanding of vesicle fate in vivo and, eventually, control. The latter was achieved by tailoring the structural characteristics of liposomes in ways that ensure both quantitative retention of entrapped solutes during exposure of the carrier to blood en route to the target, and vesicle clearance rates from the circulation that are conducive to optimal pharmacokinetics.


High Density Lipoprotein Small Unilamellar Vesicle Polysialic Acid Vesicle Stability High Density Lipoprotein Level 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Absolom, D., 1986, Opsonins and dysopsonins — an overview, Methods Enzymol 839:1.Google Scholar
  2. Black, C.D.V., and Gregoriadis, G., 1974, Intracellular fate and effect of liposome-entrapped actinomycin D injected into rats, Biochem.Soc.Trans, 2;869.Google Scholar
  3. Black, C.D.V., and Gregoriadis, G., 1976, Interaction of liposomes with blood plasma proteins, Biochem. Soc. Trans. 4:253.PubMedGoogle Scholar
  4. Bonte, F., and Juliano, R.L., 1986, Interaction of liposomes with serum proteins, Chem. Phys. Lipids, 40:359.PubMedCrossRefGoogle Scholar
  5. Fernandes, A., and Gregoriadis, G., 1996, Synthesis, characterization and properties of sialylated catalase, Biophys. Biochim. Acta, 1293:92.Google Scholar
  6. Fernandes, A., and Gregoriadis, G., 1997, Polysialylated asparaginase: preparation, activity and pharmacokinetics, Biophys. Biochim. Acta, 1341:26.CrossRefGoogle Scholar
  7. Gregoriadis, G., 1973, Drug entrapment in liposomes, FEBS Lett. 36:292.PubMedCrossRefGoogle Scholar
  8. Gregoriadis, G., 1974, Structural requirements for the specific uptake of marcomolecules and liposomes by target tissues, in: Enzyme Therapy in Lysosomal Storage Disease, J.M. Tager, G.J.M. Hooghwinkel and W.Th. Daems, eds., North-Holland Publising Co., Amsterdam.Google Scholar
  9. Gregoriadis, G., 1976a, The carrier potential of liposomes in biology and medicine, New Engl. J. Med. (Medical Progress article) 295:704.PubMedCrossRefGoogle Scholar
  10. Gregoriadis, G., 1976b, The carrier potential of liposomes in biology and medicine, New Engl. J. Med. 295:765.PubMedCrossRefGoogle Scholar
  11. Gregoriadis, G., 1995, Engineering liposomes for drug delivery: progress and problems, Trends in Biotechnology, 13:527.PubMedCrossRefGoogle Scholar
  12. Gregoriadis, G., 1998, Liposome research in drug delivery and targeting: Thoughts of an early participant, in: Medical Applications of Liposomes, D.D. Lasic and D. Papahadjopoulos, eds., Elsevier Science, BV Amsterdam.Google Scholar
  13. Gregoriadis, G., and Ryman, B.E., 1972a, Fate of protein-containing liposomes injected into rats. An approach to the treatment of storage diseases, Eur. J. Biochem., 24:485.PubMedCrossRefGoogle Scholar
  14. Gregoriadis, G., and Ryman, B.E., 1972b, Lysosomal localization of enzyme-containing liposomes injected into rats, Biochem. J. 128:142.Google Scholar
  15. Gregoriadis, G., and Buckland, R.A., 1973, Enzyme-containing liposomes alleviate a model for storage disease, Nature (London) 244:170.PubMedCrossRefGoogle Scholar
  16. Gregoriadis, G., and Neerunjun, D.E., 1974, Control of the rate of hepatic uptake and catabolism of liposome-entrapped proteins injected into rats. Possible therapeutic applications, Eur. J. Biochem. 47:179.PubMedCrossRefGoogle Scholar
  17. Gregoriadis, G., and Neerunjun, E.D., 1975, Homing of liposomes to target cells Biochem. Biophys. Res. Comm. 65:537.PubMedCrossRefGoogle Scholar
  18. Gregoriadis, G., and Davis, C, 1979, Stability of liposomes in vivo and in vitro is promoted by their cholesterol content and the presence of blood cells, Biochem. Biophys. Res. Comm. 89:1287.PubMedCrossRefGoogle Scholar
  19. Gregoriadis, G., and Senior, J., 1980, The phospholipid component of small unilamellar liposomes controls the rate of clearance of entrapped solutes from the circulation, FEBS Lett. 119:43.PubMedCrossRefGoogle Scholar
  20. Gregoriadis, G., Leathwood, P.D., and Ryman, B.E., 1971, Enzyme entrapment in liposomes, FEBS Lett. 14:95.PubMedCrossRefGoogle Scholar
  21. Gregoriadis, G., Neerunjun, D.E., and Hunt, R., 1977, Fate of a liposome-associated agent injected into normal and tumour-bearing rodents. Attempts to improve localization in tumour tissues, Life Sciences, 21:357.PubMedCrossRefGoogle Scholar
  22. Gregoriadis, G., McCormack, B., Wang, Z., and Lifely, R., 1993, Polysialic acids: Potential in drug delivery, FEBS Lett., 315:271.PubMedCrossRefGoogle Scholar
  23. Hwang, K.J., Luke, K.F.S., and Baumier, P.L., 1980, Hepatic uptake and degradation of unilamellar sphingomyelin/cholesterol liposomes: A kinetic study, Proc. Natl. Acad. Sci. USA, 77:4030.PubMedCrossRefGoogle Scholar
  24. Juliano, R.L., and Stamp, D., 1975, Effects of particle size and charge on the clearance of liposomes and liposome-encapsulated drugs, Biochem. Biophys. Res. Commun. 63:651.PubMedCrossRefGoogle Scholar
  25. Kirby, C, and Gregoriadis, G., 1980a, The effect of the cholesterol content of small unilamellar liposomes on the fate of their lipid components in vivo, Life Sciences 27:2223.PubMedCrossRefGoogle Scholar
  26. Kirby, C., Clarke, J., and Gregoriadis, G., 1980a, Effect of the cholesterol content of small unilamellar liposomes on their stability in vivo and in vitro, Biochem. J. 186:591.PubMedGoogle Scholar
  27. Kirby, C., Clarke, J., and Gregoriadis, G., 1980b, Cholesterol content of small unilamellar liposomes controls phospholipid loss to high density lipoproteins in the presence of serum, FEBS Lett. 111:324.PubMedCrossRefGoogle Scholar
  28. Krupp, I., Chobanian, A.V., and Brecher, J.P., 1976, The in vivo transformation of phospholipid vesicles to a particle resembling HDL in the rat, Biochem. Biophys. Res. Commun, 72:1251.PubMedCrossRefGoogle Scholar
  29. Large, P., and Gregoriadis. G., 1983, Phospholipid composition of small unilamellar liposomes containing melphalan influences drug action in mice bearing PC6 tumours, Biochem. Pharmacol 32:1315.PubMedCrossRefGoogle Scholar
  30. Loughrey, H.C., Bally, M.B., Reinish, L.W., and Cullis, P.R., 1990, The binding of phosphatidylglycerol liposomes to rat platelets is mediated by complement, Thromb.Haemost. 64:172.PubMedGoogle Scholar
  31. Moghimi, S.M., and Patel, H.M., 1993, Tecniques to study the opsonic effect of serum on uptake of liposomes by phagocytic cells from various organs of the RES, in: Liposome Technology, vol.3, G. Gregoriadis, ed., CRC Press, Boca Raton.Google Scholar
  32. Papahadjopoulos, D., Cowden, M., and Kimelberg, H., 1973, Role of cholesterol in membranes. Effects of phospholipid-protein interactions, membrane permeability and enzyme activity, Biophys. Biochim. Acta, 310:8.CrossRefGoogle Scholar
  33. Presant, CA., Proffitt, R.T., Turner, A.F., Williams, L.E., Winsor, D.W., Werner, J.L., Kennedy, P., Wiseman, C, Gala, K., McKenna, R.S., et al., Successful imaging of human cancer with indium111-labelled phospholipid vesicles, Cancer, 62:905.Google Scholar
  34. Richards, R.L., Gewürz, H., Siegel, J., and Alving, C.R., Interaction of C-reactive protein and complement with liposomes, J. Immunol., 112:1185.Google Scholar
  35. Rossi, J.D., and Wallace, B.A., 1983, Binding of fibronectin to phospholipid vesicles, J. Biol. Chem. 258:3327.PubMedGoogle Scholar
  36. Segal, A.W., Wills, E.J., Richmond, J.E., Slavin, G., Black, C.D.V., and Gregoriadis, G., 1974, Morphological observations on the cellular and subcellular destination of intravenously administered liposomes, Brit. J. Exp. Pathol. 55:320.Google Scholar
  37. Scherphof, G., Roerdink, G., Waite, M, and Parks, J., 1978, Disintegration of phosphatidylcholine liposomes inplasma as a result of interaction with high-density lipoproteins, Biophys. Biochim. Acta, 542:296.CrossRefGoogle Scholar
  38. Senior, J., and Gregoriadis, G., 1982, Is half-life of circulating small unilamellar liposomes determined by changes in their permeability?, FEBS Lett 145:109.PubMedCrossRefGoogle Scholar
  39. Senior, J., Gregoriadis, G., and Mitropoulos, K., 1983, Stability and clearance of small unilamellar liposomes: Studies with normal and lipoprotein-deficient mice, Biochem. Biophys.Acta 760:111.PubMedCrossRefGoogle Scholar
  40. Senior, J., Crawley, J.C.W., and Gregoriadis, G., 1985, Tissue distribution of liposomes exhibiting long half-lives in the circulation after intravenous injection, Biochim.Biophys.Acta 839:1.PubMedCrossRefGoogle Scholar
  41. Senior, J.H., Delgado, C., Fisher, D., Tilcock, C, and Gregoriadis, G., 1991, Influence of surface hydrophilicity of liposomes on their interaction with plasma proteins and clearance from the circulation: Studies with polyethylene glycol-coated vesicles, Biochim. Biophys. Acta, 1062:77.PubMedCrossRefGoogle Scholar
  42. Turner, A., Kirby, C, Senior, J., and Gregoriadis, G., 1983, Fate of cholesterol-rich unilamellar liposomes containing 111Inlabelled bleomycin after subcutaneous injection into rats, Biochim. Biophys. Acta 760:119.CrossRefGoogle Scholar
  43. Wolff, B., and Gregoriadis, G., 1984, The use of monoclonal anti-Thy, IgG, for the targeting of liposomes to AKR-A cells in vitro and in vivo, Biochim. Biophys. Acta 802:259.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Gregory Gregoriadis
    • 1
  1. 1.Centre for Drug Delivery Research, The School of PharmacyUniversity of LondonLondonEngland

Personalised recommendations