Cancer Chemotherapy and Pharmacology

, Volume 23, Issue 2, pp 81–86 | Cite as

Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin

  • J. A. E. Balazsovits
  • L. D. Mayer
  • M. B. Bally
  • P. R. Cullis
  • M. McDonell
  • R. S. Ginsberg
  • R. E. Falk
Original Articles Liposome, Doxorubicin, Cardiac Toxicity


Numerous studies have demonstrated that liposomal encapsulation decreases the life-threatening chronic and acute toxicities of doxorubicin in the face of unaltered or improved antitumor activity. Minimal attention has been paid to the encapsulation effect on the lesser toxicities of the drug, specifically the vesicant properties. In this report we assess the effect of the encapsulation of doxorubicin in an egg-yolk phosphatidylcholine (EPC) cholesterol liposome on the drug's topical toxicity. In addition, to ensure acceptable activity and reduction in toxicity comparable with those of previously assessed formulations, the cardiac and acute toxicities and antitumor activity of the liposomal doxorubicin complex were also investigated. Antitumor efficacy was assessed using the metastatic murine P815 mastocytoma model. Equivalent doses of free and encapsulated doxorubicin possessed the same antitumor activity in the prolongation of animal survival in 14-day survival studies conducted to assess the effect of liposomal encapsulation on the acute toxicity of this drug. The LD50 of liposomal doxorubicin was found to be 40 mg/kg, 53% higher than that of free doxorubicin (26 mg/kg). Histologic examination of cardiac sections taken from DBA/2J mice 7 days after a single i.v. injection of free or liposomal doxorubicin (25 mg/kg) revealed that the liposomal preparation was much less cardiotoxic. In animals receiving the free drug, edema, monocytic infiltration, and cell necrosis were evident. In contrast, those receiving the liposomal preparation demonstrated slight cellular edema but showed no evidence of cellular necrosis. To assess vesicant properties, DBA/2J mice were given a single s.c. injection (0.2 ml) of free or loposomal doxorubicin (2 mg/ml). Those receiving the free drug immediately developed erythema and edema at the injection site, which progressed to ulceration. Those receiving the liposomal complex developed slight erythema and edema but did not ulcerate at any time. All signs of irritation in this group had subsided 3 weeks postinjection. In summary, the liposomal complex used eliminated the vesicant properties of doxorubicin as well as significantly decreasing its cardiac and acute toxicities in the face of unaltered antitumor activity.


Doxorubicin Antitumor Activity Acute Toxicity Liposomal Doxorubicin Antitumor Efficacy 
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.
    Abra RM, Hunt CA (1981) Liposome distribution in vivo: III. Dose and vesicle size effects. Biochim Biophys Acta 666: 493–503Google Scholar
  2. 2.
    Averbuch SD, Gaudiano G, Koch TH, Bachan NR (1986) Doxorubicin induced skin necrosis in the swine model: protection with a novel radical dimer. J Clin Oncol 4: 99–94Google Scholar
  3. 3.
    Bosworth ME, Hunt CA (1982) Liposome deposition in vivo: II. Dose dependence. J Pharm Sci 7: 100–104Google Scholar
  4. 4.
    Calabresi P, Parks R (1975) Chemotherapy of neoplastic diseases. In: The pharmacological basis of therapeutics. MacMillan, New York, pp 1288–1290Google Scholar
  5. 5.
    Dorr R, Fritz W (1982) Drug data sheets, doxorubicin. In: Cancer chemotherapy handbook. Elsevier Science, New York, pp 388–401Google Scholar
  6. 6.
    Forssen EA, Tokes Z (1983) Improved therapeutic benefits of doxorubicin by entrapment in anionic liposomes. Cancer Res 43: 546–550Google Scholar
  7. 7.
    Forssen EA, Tokes ZA (1983) Attenuation of dermal toxicity of doxorubicin by liposome encapsulation. Cancer Treat Rep 67: 481–484Google Scholar
  8. 8.
    Gabizon A, Dagan D, Goren D, Barenholz Y, Fuks Z (1982) Liposomes as in vivo carriers of adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res 42: 4734–4739Google Scholar
  9. 9.
    Gabizon A, Goren D, Fuks Z, Barenholz A, Dagan A, Meshorer A (1983) Enhancement of adriamycin delivery to liver metastatic cells with increased tumouricidal effect using liposome as drug carriers. Cancer Res 43: 4730–4735Google Scholar
  10. 10.
    Hope MJ, Bally MB, Webb G, Cullis PR (1985) Production of large unilamellar vesicle by rapid extrusion procedure. Characterization of size, trapped volume and ability to maintain a membrane potential. Biochim Biophys Acta 812: 55–65Google Scholar
  11. 11.
    Juliano RL, Layton D (1980) Liposomes as a drug delivery system. In: Drug delivery systems: characteristics and biomedical application. Oxford University Press, London, pp 189–236Google Scholar
  12. 12.
    Knoben J, Anderson P (1983) Antineoplastic agents. In: Handbook of clinical drug data. Drug Intelligence Publications, Hamilton, p 347Google Scholar
  13. 13.
    Mayer LD, Bally MB, Cullis PR (1986a) Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient. Biochim Biophys Acta 85: 123–126Google Scholar
  14. 14.
    Mayer LD, Bally MB, Hope MJ, Cullis PR (1986b) Techniques for encapsulating bioactive agents into liposomes. Chem Phys Lipids 40: 333–345Google Scholar
  15. 15.
    Mayer LD, Hope MJ, Cullis PR, Janoff AS (1986c) Solute distributions and trapping efficiencies observed in freeze thawed multilamellar vesicles. Biochem Biophys Acta 817: 193–196Google Scholar
  16. 16.
    Mayhew E, Rustum Y (1985) The use of liposomes as carriers of therapeutic agents. In: Molecular basis of cancer, part B. Macromolecular recognition, chemotherapy, and immunology Alan Liss, New York, pp 301–310Google Scholar
  17. 17.
    Minow RA, Benjamin RS, Gottlieb JA (1975) Adriamycin cardiomyopathy: an overview with determination of risk factors. Cancer Chemother Rep 6: 195–201Google Scholar
  18. 18.
    Olson F, Mayhew E, Maslow D, Rustums Y, Szoka F (1982) Characterization, toxicity and therapeutic efficacy of adriamycin encapsulated in liposomes. Eur J Cancer 18: 167–175Google Scholar
  19. 19.
    Rahman A, Kessler A, More N, Sikic B, Rowden G, Woolley P, Schein P (1980) Liposomal protection of adriamycin induced cardiotoxicity in mice. Cancer Res 40: 1532–1537Google Scholar
  20. 20.
    Rahman A, White G, More N, Schein P (1985) Pharmacological, toxicological and therapeutic evaluation on mice of doxorubicin entrapped in cardiolipin liposomes. Cancer Res 45: 796–803Google Scholar
  21. 21.
    Senior J, Gregordiadis G (1982) Is half-life of circulating liposomes determined by changes in their permeability. FEBS Lett 145: 109–114Google Scholar
  22. 22.
    Shinozara S, Araki Y, Oov T (1981) Tissue distribution and anti-tumour effect of liposome entrapped doxorubicin (adriamycin) in Erlich solid tumor bearing mice. Acta Med Okayama 35: 395–4052Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • J. A. E. Balazsovits
    • 1
  • L. D. Mayer
    • 2
  • M. B. Bally
    • 2
  • P. R. Cullis
    • 2
  • M. McDonell
    • 1
  • R. S. Ginsberg
    • 3
  • R. E. Falk
    • 1
  1. 1.Department of SurgeryUniversity of TorontoTorontoCanada
  2. 2.The Department of BiochemistryUniversity of British ColumbiaVancouverCanada
  3. 3.Princeton Forrestal CentreThe Lipsome Company Inc.PrincetonUSA

Personalised recommendations