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The systemic activation of macrophages by liposomes containing immunomodulators

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Conclusions

The demonstration that appropriately activated macrophages can destroy microorganisms and cancer cells has prompted an intense search to identify agents which can render these cells active in vivo. Several natural products, e. g., lymphokines or synthetic molecules, e. g., MDP can produce the tumoricidal state in macrophages. The in vivo use of these agents has been limited, since they have a very short half life.

Liposomes offer a most useful carrier system to transport agents to phagocytic cells in vivo. Once in the circulation, liposomes are cleared by phagocytic cells and this passive localization provides an effective mechanism for targeting liposome-entrapped materials to macrophages. In this review we have described the exploitation of this mechanism to deliver lymphokines or other synthetic molecules to macrophages in situ. Since not all liposomes home equally to macrophages, there is still a great need to identify vesicles with ideal properties for this task. The potential application of liposome encapsulated agents to activate macrophages is tremendous. Only future studies will determine the effectiveness and limitations for activated macrophages in enhancing host defense against infections and cancer.

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References

  1. Allison AC (1979) Mode of action of immunological adjuvants. J Reticuloendothel Soc 26: 619

    PubMed  Google Scholar 

  2. Alving CR (1983) Delivery of liposome-encapsulated drugs to macrophages. Pharmacol Ther 22:407

    PubMed  Google Scholar 

  3. Bally MB, Hope MJ, van Echteld CIA, Cullis PR (1985) Uptake of safranine and other lipophilic cations into model membrane systems in response to a membrane potential. Biochim Biophys Acta 812: 66

    Google Scholar 

  4. Chedid L, Audibert F, Johnson AG (1978) Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog Allergy 25: 63

    PubMed  Google Scholar 

  5. Cifone MA, Fidler IJ (1981) Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA 78: 6949

    PubMed  Google Scholar 

  6. Den Otter W, Dullens Hub FJ, Van Lovern H, Peib E (1977) Anti-tumor effects of macrophagesv injected into animals: A review. In: James K, McBride B, Stuart A (eds) The macrophage and cancer. Econoprint, Edinburgh, p 119

    Google Scholar 

  7. Deodhar SD, Banna BP, Edinger M (1982) Inhibition of lung metastasis by liposomal immunotherapy in a murine fibrosarcoma model. J Biol Respnse Mod 1: 27

    Google Scholar 

  8. Fidler IJ (1974) Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages. Cancer Res 34: 1074

    PubMed  Google Scholar 

  9. Fidler IJ, Fogler WE (1982) Activation of tumoricidal properties in macrophages by lymphokines encapsulated in liposomes. Lymphokine Res 1: 73

    PubMed  Google Scholar 

  10. Fidler IJ, Hart IR (1982) Biological diversity in metastatic neoplasms: Origins and implications. Science 217: 998

    PubMed  Google Scholar 

  11. Fidler IJ, Kleinerman ES (1984) Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions. J Clin Oncol 2: 937

    PubMed  Google Scholar 

  12. Fidler IJ, Kripke ML (1977) Metastasis results from preexisting variant cells within a malignant tumor. Science 197: 893

    PubMed  Google Scholar 

  13. Fidler IJ, Poste G (1982) Macrophage-mediated destruction of malignant tumor cells and new strategies for therapy of metastatic disease. Springer Semin Immunopathol 5: 161

    PubMed  Google Scholar 

  14. Fidler IJ, Schroit AJ (1984) Synergism between lymphokines and muramyl dipeptide encapsulated in liposomes: In situ activation of macropbages and therapy of spontaneous cancer metastases. J Immunol 133: 515

    PubMed  Google Scholar 

  15. Fidler IJ, Roblin RO, Poste G (1978) In vitro tumoricidal activity of macrophages against virustransformed lines with temperature-dependent transformed phenotypic characteristis. Cell Immunol 38: 131

    PubMed  Google Scholar 

  16. Fidler IJ, Fogler WE, Connor J (1979) The rationale for the treatment of established experimental micrometastases with the injection of tumoricidal macrophages. In: Terry WE, Yamamura Y (eds) Immunobiology and immunotherapy of cancer. Elsevier, New York, p 361

    Google Scholar 

  17. Fidler IJ, Raz A, Fogler WE, Kirsh R, Bugelski P, Poste G (1980) The design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages. Cancer Res 40: 4460

    PubMed  Google Scholar 

  18. Fidler IJ, Raz A, Fogler WE, Hoyer LC, Poste G (1981) The role of plasma membrane receptors and the kinetics of macrophage activation by lymphokines encapsulated in liposomes. Cancer Res 41:495

    PubMed  Google Scholar 

  19. Fidler IJ, Sone S, Fogler WE, Barnes ZL (1981) Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78: 1680

    PubMed  Google Scholar 

  20. Fidler IJ, Barnes Z, Fogler WE, Kirsh R, Bugelski P, Poste G (1982) Involvement of macrophages in the eradication of established metastasis following intravenous injection of liposomes containing macrophage activators. Cancer Res 42: 496

    PubMed  Google Scholar 

  21. Fidler IJ, Sone S, Fogler WE, Smith D, Braun DA, Tarcsey L, Gisler RH, Schroit AJ (1982) Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo. J Biol Response Mod 1: 43

    Google Scholar 

  22. Fidler IJ, Fogler WE, Tarcsey L, Schumann G, Braun DG, Schroit AJ (1983) Systemic activation of macrophages and treatment of cancer metastases by liposomes containing hydrophilic or lipophilic muramyl dipeptide. In: Hadden JW (ed) Advances in immunopharmacology, vol. 2. Pergamon Press, New York, p 235

    Google Scholar 

  23. Fogler WE, Fidler IJ (1984) Modulation of the immune response by muramyl dipeptide. In: Fenichel RE, Chirigos MA (eds) Immune modulation agents and their mechanisms. Macel Dekker, New York

    Google Scholar 

  24. Fogler WE, Fidler IJ (1985) Nonselective destruction of murine neoplastic cells by syngeneic tumoricidal macrophages. Cancer Res 45: 14

    PubMed  Google Scholar 

  25. Gregoriadis G, Allison AC (eds) Liposomes in biological systems. Wiley Interscience, New York

  26. Guo LSS, Hamilton RE, Goerke J, Weistein JN, Havel RJ (1980) Interaction of unilamellar liposomes with serum lipoproteins and apolipoproteins. J Lipid Res 21: 993

    PubMed  Google Scholar 

  27. Hart IR, Fogler WE, Poste G, Fidler IJ (1981) Toxicity studies of liposome-encapsulated immunomodulators administered intravenously to dogs and mice. Cancer Immunol Immunother 10: 157

    Google Scholar 

  28. Hope MJ, Bally MB, Webb G, Cullis PR (1985) Production of large unilamellar vesicles by a rapid extrusion procedure. Biochim Biophys Acta 812: 55

    Google Scholar 

  29. Kao YJ, Juliano RL (1981) Interaction of liposomes with the reticuloendothelial system: Effects of reticuloendothelial blockade on the clearance of large unilamellar vesicles. Biochim Biophys Acta 677: 453

    PubMed  Google Scholar 

  30. Key ME, Talmadge JE, Fogler WE, Bucana C, Fidler IJ (1982) Isolation of tumoricidal macrophages from lung melanoma metastases of mice treated systemically with liposomes containing a lipophilic derivative of muramyl dipeptide. JNCI 69: 1189

    Google Scholar 

  31. Kleinerman ES, Fidler IJ (1983) Production and utilization of human lymphokines containing macrophage-activating factor (MAF) activity. Lymphokine Res 2: 7

    PubMed  Google Scholar 

  32. Kleinerman ES, Schroit AJ, Fogler WE, Fidler IJ (1983) Tumoricidal activity of human monocytes activated in vitro by free and liposome-encapsulated human lymphokines. J Clin Invest 72: 304

    PubMed  Google Scholar 

  33. Knight CG (eds) (1981) Liposomes from physical structure to therapeutic applications. Elsevier/North Holland, Amsterdam

    Google Scholar 

  34. Koff WC, Fidler IJ (to be published) The potential use of liposome mediated antiviral therapy. Antiviral Res

  35. Koff WC, Fogler WE, Gutterman J, Fidler IJ (to be published) Efficient activation of human blood monocytes to a tumoricidal state by liposomes containing human recombinant gamma interferon. Cancer Immunol Immunother

  36. Liotta LA, Gattozzi C, Kleinerman J, Saidal G (1977) Reduction of tumor cell entry into vessels by BCG-activated macrophages. Br J Cancer 36: 639

    PubMed  Google Scholar 

  37. Lopez-Berestein G, Kasi L, Rosenblum MG, Haynie T, Johns M, Glenn H, Mehta R, Mauligit GM, Hersh EM (1984) Clinical pharmacology of99mTc-labeled liposomes in patients with cancer. Cancer Res 44: 375

    PubMed  Google Scholar 

  38. Lopez-Berestein G, Mehta K, Mehta R, Juliano RL, Hersh EM (1983) The activation of human monocytes by liposome-encapsulated muramyl dipeptide analogues. J Immunol 130: 1500

    PubMed  Google Scholar 

  39. Lopez-Berestein G, Milas L, Hunter N, Mehta K, Hersh EM, Kurahara CG, Vanderpas M, Eppstein DA (1984) Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-0-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine. Clin Exp Metastasis 2: 127

    PubMed  Google Scholar 

  40. Machy P, Leserman LD (1983) Small liposomes are better than large liposomes for specific drug delivery in vitro. Biochim Biophys Acta 730: 313

    PubMed  Google Scholar 

  41. Mehta K, Lopez-Berestein G, Hirsh EM, Juliano SL (1982) Uptake of liposomes and liposomeencapsulated muramyl dipeptide by human peripheral blood monocytes. J Reticuloendothel Soc 32: 155

    PubMed  Google Scholar 

  42. Papermaster BW, Holterman OA, Rosner D, Klein E, Dao T, Djerassi I (1974) Regressions producted in breast cancer lesions by a lymphokine fraction from a human lymphoid cell line. Res Commun Chem Pathol Pharmacol 8: 413

    PubMed  Google Scholar 

  43. Parant M, Parant F, Chedid L, Yapo A, Petit JF, Lederer E (1979) Fate of the synthetic immunoadjuvant muramyl dipeptide (14C-labeled) in the mouse. Int J Immunopharmacol 1: 35

    PubMed  Google Scholar 

  44. Philips NC, Mores ML, Chedid L, Lefrancier JM (1985) Activation of alveolar macrophage tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative. Cancer Res 45: 128

    PubMed  Google Scholar 

  45. Poste G (1983) Liposome targeting in vivo: Problems and opportunities. Biol Cell 47: 19

    Google Scholar 

  46. Poste G, Fidler IJ (1979) The pathogenesis of cancer metastasis. Nature 283: 139

    Google Scholar 

  47. Poste G, Bucana C, Raz A, Bugelski P, Kirsh R, Fidler IJ (1982) Analysis of the fate of systemically administered liposomes and implications for their use in drug deliverly. Cancer Res 42: 1412

    PubMed  Google Scholar 

  48. Raz A, Bucana C, Fogler WE, Poste G, Fidler IJ (1981) Biochemical, morphological, and ultrastructural studies on the uptake of liposomes by murine macrophages. Cancer Res 41: 487

    PubMed  Google Scholar 

  49. Ritter C, Rutman RJ (1984) Liposome as active participants in experimental therapeutics. Cancer Drug Delivery 1: 137

    PubMed  Google Scholar 

  50. Scherphof G, Roerdink F, Dijkstre J, Ellens H, DeZander R, Wisse E (1983) Uptake of liposomes by rat and mouse hepatocytes and Kupffer cells. Biol Cell 47: 47

    Google Scholar 

  51. Schroit AJ, Fidler IJ (1982) Effects of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42: 161

    PubMed  Google Scholar 

  52. Schroit AJ, Fidler IJ (to be published) The use of activated macrophages for the destruction of heterogeneous metastases. In: Horn KV (ed) Mechanisms of metastasis. Martinus Nijhoff Publishers, Amsterdam

  53. Schroit AJ, Galligioni E, Fidler IJ (1983) Factors influencing the in situ activation of macrophages by liposomes containing muramyl dipeptide. Biol Cell 47: 87

    Google Scholar 

  54. Shulkin PM, Seltzer SS, Davis MA, Adamd DF (1984) Lyophilized liposomes: A new method for long-term vesicular storage. J Microencap 1: 73

    Google Scholar 

  55. Sone S, Fidler IJ (1980) Synergistic activation by lymphokines and muramyl dipeptide of tumoricidal properties in rat alveolar macrophages. J Immunol 125: 2454

    PubMed  Google Scholar 

  56. Sone S, Fidler IJ (1981) In vitro activation of tumoricidal properties in rat alveolar macrophages by synthetic muramyl dipeptide encapsulated in liposomes. Cell Immunol 57: 42

    PubMed  Google Scholar 

  57. Straubinger RM, Duzgunes N, Papahadjopoulos (1985) pH-sensitive liposomes mediate cytoplasmic delivery of encapsulated macromolecules. FEBS Lett 179: 148

    PubMed  Google Scholar 

  58. Sullivan SM, Huang L (1985) Preparation and characterization of heat-sensitive immunoliposomes. Biochim Biophys Acta 812: 116

    PubMed  Google Scholar 

  59. Szoka FC, Papahadjopoulos D (1978) Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci USA 75: 4194

    PubMed  Google Scholar 

  60. Szoka FC, Papahadjopoulos D (1980) Comparative properties and methods of preparation of lipid vesicles (liposomes). Annu Rev Biophys Bioeng 9: 467

    PubMed  Google Scholar 

  61. Talmadge JE, Wolman SR, Fidler IJ (1982) Evidence for the clonal origin of spontaneous metastases. Science 217: 361

    PubMed  Google Scholar 

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Nayar, R., Fidler, I.J. The systemic activation of macrophages by liposomes containing immunomodulators. Springer Semin Immunopathol 8, 413–428 (1985). https://doi.org/10.1007/BF01857394

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