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Basic Sciences

Liposomes as in Vivo Carriers of Adriamycin: Reduced Cardiac Uptake and Preserved Antitumor Activity in Mice

A. Gabizon, A. Dagan, D. Goren, Y. Barenholz and Z. Fuks
A. Gabizon
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A. Dagan
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D. Goren
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Y. Barenholz
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Z. Fuks
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DOI:  Published November 1982
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Abstract

Neutral and negatively charged liposomes containing Adriamycin (ADM) were examined for the efficiency of drug entrapment, serum stability, in vivo tissue distribution, and tumor-inhibitory activity. Entrapment of ADM in negatively charged liposomes containing phosphatidylserine (PS) or cardiolipin (DPG) was 3- to 4-fold higher than in neutral phosphatidylcholine (PC) liposomes with or without cholesterol (Chol). In the presence of human serum, PC:Chol and PS:PC:Chol liposomes were more stable than DPG:PC:Chol liposomes, as measured by the degree of release of entrapped drug. Tissue distribution studies after i.v. injection of liposome-entrapped ADM into mice indicated that the levels of ADM were increased severalfold in the liver and the spleen. Concomitantly, the concentration of ADM in the heart was significantly diminished when the drug was delivered by PS:PC:Chol and PC:Chol liposomes but only slightly reduced when DPG:PC:Chol liposomes were used. In vitro studies with primary cell cultures of a murine lymphoma showed that the cytotoxic activity of ADM was fully preserved with the various ADM-containing liposomes used. Finally, the in vivo antitumor activity of liposome-entrapped ADM was tested on a metastatic murine lymphoma. Large multilamellar PS:PC:Chol:ADM and PC:Chol:ADM liposomes, given as a single i.v. injection, were as effective in prolonging survival as equivalent doses of free ADM. Repeated i.v. injections of small sonicated PS:PC:Chol:ADM liposomes resulted in a significantly improved survival compared to free ADM. These results indicate that the delivery of ADM by certain types of liposomes may offer an efficient means of restricting its cardiac uptake and possibly minimizing its cardiotoxicity, while preserving its antitumor therapeutic activity.

Footnotes

  • ↵1 This work was supported by the Israel National Council for Research and Development and by the Israel Cancer Research Fund.

  • ↵2 To whom requests for reprints should be addressed, at Department of Radiation and Clinical Oncology, Hadassah University Hospital, P. O. Box 12000, Kiryat Hadassah, Jerusalem, Israel 91120.

  • Received January 5, 1982.
  • Accepted August 6, 1982.
  • ©1982 American Association for Cancer Research.
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November 1982
Volume 42, Issue 11
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Liposomes as in Vivo Carriers of Adriamycin: Reduced Cardiac Uptake and Preserved Antitumor Activity in Mice
A. Gabizon, A. Dagan, D. Goren, Y. Barenholz and Z. Fuks
Cancer Res November 1 1982 (42) (11) 4734-4739;

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Liposomes as in Vivo Carriers of Adriamycin: Reduced Cardiac Uptake and Preserved Antitumor Activity in Mice
A. Gabizon, A. Dagan, D. Goren, Y. Barenholz and Z. Fuks
Cancer Res November 1 1982 (42) (11) 4734-4739;
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