Skip to main content
SpringerLink
Log in

Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia

  • Original Articles
  • Vincristine, Liposomes, L1210 Leukemia
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The influence of vesicle lipid composition, size and drug-to-lipid ratio on the antitumour activity of liposomal vincristine was assessed in the murine L1210 ascitic leukemia model. A pH gradient-dependent entrapment procedure was used to encapsulate vincristine and allowed such vesicle properties to be independently varied. Free vincristine delivered i.v. at the maximum tolerated dose (2.0 mg/kg) resulted in a 27.8% increase in the life span (ILS) of mice inoculated i.p. with L1210 cells. Encapsulation of the drug in egg phosphatidylcholine/cholesterol vesicles did not significantly increase the antitumour efficacy of vincristine (ILS, 38.9%). In contrast, administration of vincristine entrapped in vesicles composed of distearoylphosphatidylcholine (DSPC)/cholesterol resulted in ILS values as high as 133%. This enhanced antitumour activity of the DSPC/cholesterol formulations was sensitive to the size of the liposomes; increasing the vesicle size from 100 nm to 1 μm decreased the ILS from 133.3% to 55.6% at a drug dose of 2.0 mg/kg. Decreasing the drug-to-lipid ratio from 0.1∶1 to 0.05∶1 (w/w) had negligible effects on the activity of liposomal vincristine; however, a further decrease in the drug-to-lipid ratio to 0.01∶1 (w/w) decreased the antitumour potency at all drug doses studied. Pharmacology studies indicated that the antitumour activities of free and various liposomal forms of vincristine correlated well with the residence time of the drug in the circulation. These studies indicate that efforts to enhance the therapeutic activity of vincristine through liposome encapsulation must address not only the circulation life-time of the vesicle systems but also the capacity of the liposomes to retain entrapped drug in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

HPLC:

high-pressure liquid chromatography

MLV:

multilamellar vesicle

EPC:

egg phosphatidylcholine

DSPC:

distearoylphosphatidylcholine

CHOL:

cholesterol

VINC:

vincristine

HBSS:

Hanks' balanced salt solution

References

  1. Abra RM, Hunt CA (1981) Liposome disposition in vivo. III. Dose and vesicle size effects. Biochim Biophys Acta 666: 493–503

    Google Scholar 

  2. Allen TM, Mehra T, Hansen C, Chin YC (1992) Stealth liposomes: an improved sustained release system for 1-β-D-arabinofuranosylcytosine. Cancer Res 52: 2431–2439

    Google Scholar 

  3. Bally MB, Nayar R, Masin D, Hope MJ, Cullis PR, Mayer LD (1990) Liposomes with entrapped doxorubicin exhibit extended blood residence times. Biochim Biophys Acta 1023: 133–139

    Google Scholar 

  4. Beaumier PL, Hwang KJ (1983) Effects of liposome size on the degradation of bovine brain sphingomyelin/cholesterol liposomes in mouse liver. Biochim Biophys Acta 731: 23–30

    Google Scholar 

  5. Beaumier PL, Hwang KJ, Slattery JT (1983) Effect of liposome dose on the elimination of small unilamellar sphingomyelin/cholesterol vesicles from the circulation. Res Commun Chem Pathol Pharmacol 309: 277–289

    Google Scholar 

  6. Bosworth ME, Hunt CA (1982) Liposome disposition in vivo. II. Dose dependency. J Pharmacol Sci 71: 100–104

    Google Scholar 

  7. Forssen EA, Tokes ZA (1981) Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity. Proc Natl Acad Sci USA 78: 1873–1877

    Google Scholar 

  8. Gabizon AA (1992) Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res 52: 891–896

    Google Scholar 

  9. Gabizon A, Paphadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85: 6949–6953

    Google Scholar 

  10. Gabizon A, Meshorer A, Barenholz Y (1986) Comparative long-term study of the toxicities of free and liposome-associated doxorubicin in mice after intravenous administration. J Natl Cancer Inst 77: 459–467

    Google Scholar 

  11. Gabizon A, Price DC, Huberty J, Bresalier RS, Papahadjopoulos D (1990) Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies. Cancer Res 50: 6371–6378

    Google Scholar 

  12. Gregoriadis G (1988) Preface in: Gregoriadis G (ed) Liposomes as drug carriers. John Wiley and Sons, New York, pp XXV-XXVI

    Google Scholar 

  13. Herman EH, Rahman A, Ferrans VJ, Vick JA, Schein PS (1985) Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation. Cancer Res 45: 5427–5432

    Google Scholar 

  14. Horton JK, Houghton PJ, Houghton JA (1988) Relationships between tumor responsiveness, vincristine pharmacokinetics and arrest of mitosis in human tumor xenografts. Biochem Pharmacol 37: 3995–4000

    Google Scholar 

  15. Horton JK, Thimmaiah KN, Houghton JA, Horowitz ME, Houghton PJ (1989) Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts. Biochem Pharmacol 38: 1727–1736

    Google Scholar 

  16. Houghton JA, Williams LG, Dodge RK, George SL, Hazelton BJ, Houghton PJ (1987) Relationship between binding affinity, retention and sensitivity of human rhabdomyosarcoma xenografts to vinca alkaloids. Biochem Pharmacol 36: 81–88

    Google Scholar 

  17. Hwang KJ (1987) Liposome pharmacokinetics. In: Ostro MJ (ed) Liposomes: from biophysics to therapeutics. Marcel Dekker, New York, pp 109–156

    Google Scholar 

  18. Jackson DV, Bender RA (1979) Cytotoxic thresholds of vincristine in a murine and a human tumor leukemia cell line in vitro. Cancer Res 39: 4346–4349

    Google Scholar 

  19. Jackson DV, Sethi VS, Spurr CL, Willard V, White DR, Richards F, Stuart JJ, Muss HB, Cooper R, Homesley HD, Jobson VW, Castle MC (1981) Intravenous vincristine infusion: phase I trial. Cancer 48: 2559–2564

    Google Scholar 

  20. Jackson DV, Paschold EH, Spurr CL, Muss HB, Richards F, Cooper MR, White DR, Stuart JJ, Hopkins JO, Rich R, Wells HB (1984) Treatment of advanced non-Hodgkin's lymphoma with vincristine infusion. Cancer 53: 2601–2606

    Google Scholar 

  21. Mayer LD, Hope MJ, Cullis PR (1986) Vesicles of various sizes produced by a rapid extrusion procedure. Biochim Biophys Acta 858: 161–168

    Google Scholar 

  22. Mayer LD, Hope MJ, Cullis PR, Janoff AS (1986) Solute distributions and trapping efficiencies observed in freeze-thawed multilamellar vesicles. Biochim Biophys Acta 817: 193–196

    Google Scholar 

  23. Mayer LD, Tai LCL, Ko DSC, Masin C, Ginsberg RS, Cullis PR, Bally MB (1989) Influence of vesicle size, lipid composition and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res 49: 5922–5930

    Google Scholar 

  24. Mayer LD, Tai LCL, Bally MB, Mitilenes GN, Ginsberg RS, Cullis PR (1990) Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim Biophys Acta 1025: 143–151

    Google Scholar 

  25. Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT (1990) Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett 53: 183–190

    Google Scholar 

  26. Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR (1990) Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res 50: 575–579

    Google Scholar 

  27. Olson F, Mayhew E, Maslow D, Rustum Y, Szoka F (1982) Characterization, toxicity and therapeutic efficacy of Adriamycin encapsulated in liposomes. Eur J Cancer Clin Oncol 18: 4734–4739

    Google Scholar 

  28. Ostro MJ (1987) Introduction in: Ostro MJ (eds) Liposomes, from biophysics to therapeutics. Marcel Dekker, New York, pp VII-X

    Google Scholar 

  29. Proffitt RT, Williams LE, Presant CA, Tin GW, Uliana JA, Gamble GC, Baldeschweiler JD (1983) Tumor imaging potential of liposomes loaded with In-111-NTA: biodistribution in mice. J Nucl Med 24: 45–51

    Google Scholar 

  30. Rahman A, Kessler A, More N, Sikic B, Rowden G, Woolley P, Schein PS (1980) Liposomal protection of Adriamycin-induced cardiotoxicity in mice. Cancer Res 40: 1532–1537

    Google Scholar 

  31. Senior J, Crawley SCW, Gregoriadis C (1985) Tissue distribution of liposomes exhibiting long half lives in the circulation after intravenous injection. Biochim Biophys Acta 839: 1–8

    Google Scholar 

  32. Van Hossel QGCM, Steerenberg PA, Crommelin DJA, Dijk A van, Oost W van, Klein S, Douze JMC, Wildt DJ de, Hillen FC (1984) Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in the LOU/m WSL rat. Cancer Res 44: 3698–3705

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, V6T 1W5, Vancouver, B.C., Canada

    Lawrence D. Mayer & Robert L. Thies

  2. Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, V5Z 4B6, Vancouver, B.C., Canada

    Lawrence D. Mayer & Marcel B. Bally

  3. Miles Cutter Biologics, Inc., 4th and Parker Streets, P.O. Box 1986, 94701, Berkeley, CA, USA

    Rajiv Nayar

  4. Department of Biochemistry, University of British Columbia, 2146 Health Sciences Mall, V6T 1W5, Vancouver, B.C., Canada

    Nancy L. Boman & Pieter R. Cullis

Authors
  1. Lawrence D. Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajiv Nayar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert L. Thies
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy L. Boman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pieter R. Cullis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marcel B. Bally
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by the National Cancer Institute of Canada and The Liposome Company, Inc. (Princeton, N.J.), One of the authors (P.R.C.) is a Canadian Medical Research Council Scientist, and another (M.B.B.), is a B.C. Health Research Foundation Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mayer, L.D., Nayar, R., Thies, R.L. et al. Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia. Cancer Chemother. Pharmacol. 33, 17–24 (1993). https://doi.org/10.1007/BF00686017

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686017

Keywords

Search

Navigation