Stealth™ Liposomes as Carriers of Doxorubicin

  • Dorit Goren
  • Samuel Zalipsky
  • Aviva T. Horowitz
  • Alberto Gabizon
Part of the NATO ASI Series book series (NSSA, volume 300)


Liposomes, as non-covalently bound carriers, biocompatible and biodegradable, have raised considerable interest as a drug delivery system in cancer chemotherapy (Gregoriadis, 1988). Most applications of liposomes in cancer chemotherapy are directed at altering tissue distribution and various pharmacokinetic parameters of the drug in question in such a way that toxicity can be reduced and/or efficacy increased (Mayhew and Papahadjopoulos, 1983). Reduced toxicity may be gained through site circumvention of drug sensitive tissues and by slow release of the cytotoxic agent from the carrier, avoiding peak plasma concentrations after bolus injection of free drug. Liposome- mediated decrease in toxicity could enable escalation of dose, which will result in increased tumor exposure to the drug.


Ascitic Fluid Liposomal Doxorubicin Liposomal Drug Free Doxorubicin Anionic Liposome 
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  1. Allen, T.M., Hansen, C.B., and Guo, L.S.S., 1993, Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection. Biochim. Biophys. Acta, 1150:9.PubMedCrossRefGoogle Scholar
  2. Cabanes, A., Tzemach, D., Goren, D., Horowitz, A.T., and Gabizon A., 1998, Comparative study of the anti-tumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model, Clin. Cancer Res. 4:499.PubMedGoogle Scholar
  3. Forssen, E.A., and Tokes, Z.A., 1981, Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity, Proc Natl Acad Sci 78:1873.PubMedCrossRefGoogle Scholar
  4. Forssen, E.A., and Tokes, Z.A., 1983, Improved therapeutic benefits of doxorubicin by entrapment in anionic liposomes, Cancer Res. 43:546.PubMedGoogle Scholar
  5. Gabizon, A., 1992, Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes, Cancer Res. 52:891.PubMedGoogle Scholar
  6. Gabizon, A., 1995, Liposome circulation time and tumor targeting:implications for cancer chemotherapy, Adv. Drug DelivRev. 16:285.CrossRefGoogle Scholar
  7. Gabizon, A., Meshorer, A., and Barenholz, Y., 1986b, Comparative long term study of the toxicities of free and liposomes associated doxorubicin in mice after intravenous administration, J.Natl. Cancer Inst. 77:459.PubMedGoogle Scholar
  8. Gabizon, A., Goren, D., and Barenholz, Y., 1988a, Investigation on the antitumor efficacy of liposome-associated doxorubicin in murine tumor models, Isr. J. Med Sci. 24:517.Google Scholar
  9. Gabizon, A., Barenholz, Y., and Bialer, M, 1993a, Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: Pharmacokinetic studies in rodents and dogs, Pharm. Res. 10:703.PubMedCrossRefGoogle Scholar
  10. Gabizon, A., Goren, D., Ramu, A., and Barenholz, Y., 1986a, Design, characterization and anti-tumor acticity of adriamycin containing phospholipid vesicles, In: Targeting of Drugs with Synthetic Systems, G. Gregoriadis, J. Senior, G. Poste eds., Plenum, London.Google Scholar
  11. Gabizon, A., Goren, D., Fuks, Z., Meshorer, A., and Barenholz, Y., 1985, Superior therapeutic activity of liposome associated adriamycin in a murine metastatic tumor model, Br.J. Cancer, 51:681.PubMedCrossRefGoogle Scholar
  12. Gabizon, G., Goren, D., Fuks, Z., Barenholz, Y., Dagan, A., and Meshorer, A., 1983, Enhancement of adriamycin delivery to liver metastatic cells with increased tumoricidal effect using liposomes as drug carriers, Cancer Res. 43:4730.PubMedGoogle Scholar
  13. Gabizon, A., Dagan, A., Goren, D., Barenholz, Y., and Fuks, Z., 1982, Liposomes as in vivo carriers of adriamycin: Reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res. 42:4734.PubMedGoogle Scholar
  14. Gabizon, A., Pappo, O., Goren, D., Chemla, M, Tzemach, D., and Horowitz, A.T., 1993b, Preclinical studies with doxorubicin encapsulated in polyethylene glycol-coated liposomes, J. Liposome Res. 3:517.CrossRefGoogle Scholar
  15. Gabizon, G., Chemla, M., Tzemach, D., Horowitz, A.T., and Goren, D., 1996, Liposome longevity and stability in circulation: effects on the in vivo delivery to tumors and therapeutic efficacy of encapsulated anthracyclines, J. Drug Targeting, 3:391.CrossRefGoogle Scholar
  16. Gabizon, A., Goren, D., Horowitz, A.T., Tzemach, D., Lossos, A., and Siegal, T., 1997, Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals, Adv. Drug Deliv. Rev. 24:337.CrossRefGoogle Scholar
  17. Gabizon, A., Catane, R., Uziely, B., Kaufman, B., and Barenholz, Y., 1994, Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes, Cancer Res. 54:987.PubMedGoogle Scholar
  18. Goren, D., Horowitz, A.T., Zalipsky, S., Woodle, M.C., Yarden, Y., and Gabizon, A., 1996, Targeting of Stealth liposomes to erbB2 (Her/2) receptor: in vitro and in vivo studies. Br.J. Cancer, 74:1749.PubMedCrossRefGoogle Scholar
  19. Goren, D., Horowitz, A.T., Mandelbaum-Shavit, F., Tzemach, D., Zalipsky, S., and Gabizon, A., 1997, In vitro and in vivo studies of folate-targeted liposomes, Proc.Cont. Rel. Soc. 24:865.Google Scholar
  20. Gregoriadis, G., ed., 1988, Liposomes as Drug Carriers: Recent Trends and Progress, Wiley, London.Google Scholar
  21. Haran, G., Cohen, R., Bar., L.K. and Barenholz, Y., 1993, Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases, Biochim. Biophys. Acta,1151:201.PubMedCrossRefGoogle Scholar
  22. Harrison, D., Tomlinson, D., and Stewart, S., 1995, Liposomal entrapped doxorubicin:an active agent in aids-related Kaposi’s sarcoma, J. Clin. Oncol. 13:914.PubMedGoogle Scholar
  23. Van Hoesel, Q.G., Steerenberg, P.A., Crommelin, D.J., Van Dijk, A., Van Oort, W., Klein, S., Douze, J.M., de Wildt, DJ., and Hillen, F.C., 1984, Reduced cardiotoxicity and nephrotoxicity with preservation of anti-tumor activity of doxorubicin entrapped in stable liposomes in the Lou/M Ws1 Rat, Cancer Res. 44:3698.PubMedGoogle Scholar
  24. Lasic, D., and Martin, F., eds., 1995, Stealth Liposomes, Pharmacology and Toxicology series, CRC Press, Boca Raton, FL.Google Scholar
  25. Lasic, D.D., Frederik, P.M., Stuart, M.C., Barenholz, Y., and McIntosh, T.J., 1992, Gelation of liposome interior a novel method for drug encapsulation, FEBS Lett. 312:255.PubMedCrossRefGoogle Scholar
  26. Lee, R.J., and Low, P.S., 1994, Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis, J. Biol. Chem. 269:3198.PubMedGoogle Scholar
  27. Legha, S.S., Benjamin, R.S., Mackay, B., et al., 1982, Reduction of doxorubicin cardiotoxicity by prolonged continuous infusion, Ann Intern. Med 96:133.PubMedCrossRefGoogle Scholar
  28. Mayer, L.D., Tai, L.C., Bally, M.B., Mitilens, G.N., Ginsberg, R.S., and Cullis, P.R., 1990, Characterization of liposomal systems containing doxorubicin entrapped in response to pH gardients, Biochim.Biophys. Acta, 1025:143.PubMedCrossRefGoogle Scholar
  29. Mayhew, E., and Papahadjopoulos, D., 1983, Therapeutic application of liposomes. In: Liposomes, M.J. Ostro, ed., Marcel Dekker, New-York.Google Scholar
  30. Minow, R.A., Benjamin, R.S., and Gottlieb, J.A., 1975, Adriamycin cardiomyopathy; an overview with determination of risk factors, Cancer Chemother. Rep. 6:195.Google Scholar
  31. Muggia, F.M., Hainsworth, J.D., Jeffers, S., Miller, P., et al., and Liang.-Jung, L.J., 1997, Phase II study of liposomal doxorubicin in refractory ovarian carcinoma: anti-tumor activity and toxicity modification by liposomal encapsulation, J. Clin. Oncol. 15:987.Google Scholar
  32. Olson, F., Mayhew, E., Maslow, D., Rustum, Y., and Szoka, F., 1982, Characterization, toxicity and therapeutic efficacy of adriamycin encapsulated in liposomes, Eur J. Cancer Clin. Oncol. 18:167.PubMedCrossRefGoogle Scholar
  33. Rahman, A., White, G., More, N., and Schein, P.S., 1985, Pharmacological, toxocological and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes, Cancer Res. 45:769.Google Scholar
  34. Rahman, A., Fumagali, A., Barbieri, B., Schein, P.S., and Casazza, A.M., 1986, Anti-tumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes, Cancer Chemother. Pharmacol. 16:22.PubMedGoogle Scholar
  35. Ranson, M.R., Carmichael, J., O’Byrne, K., Stewart, S., Smith, D., and Howell, A., 1997, Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J. Clin. Oncol. 15:3185.PubMedGoogle Scholar
  36. Torchilin, V.P., 1995, Long circulating drug delivery systems, Adv. Drug Deliv. Rev. 16:125.CrossRefGoogle Scholar
  37. Unezaki, S., Maruyama, K., Ishido, O., Suginaka, A., Hosoda, J., and Iwatsuru, M., 1995, Enhanced tumor targeting and improved antitumor activity of doxorubicin by long-circulating liposomes containing amphipathic poly(ethyleneglycol), Int. J. Pharm. 126:41.CrossRefGoogle Scholar
  38. Uziely, B., Jeffers, S., Isacson, R., Kutsch, K., Wei-Tsao, D., Yehoshua, Z., Muggia, F.M., and Gabizon, A., 1995, Liposomal doxorubicin: anti-tumor activity and unique toxicities during two complementary phase I studies, J. Clin. Oncol. 13:1777.PubMedGoogle Scholar
  39. Young, R.C., Ozols, R.F., and Myers, C.E., 1981, The anthracycline anti-neoplastic drugs, N. Engl. J.Med. 305:139.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Dorit Goren
    • 1
  • Samuel Zalipsky
    • 2
  • Aviva T. Horowitz
    • 1
  • Alberto Gabizon
    • 1
  1. 1.Department of OncologyHadassah Hebrew University HospitalJerusalemIsrael
  2. 2.Sequus Pharmaceuticals Inc.Menlo ParkUSA

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