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Improved Therapeutic Benefits of Doxorubicin by Entrapment in Anionic Liposomes¹

Comprehensive Cancer Center and Department of Biochemistry, University of Southern California, Los Angeles, California 90033

³ To whom all correspondence should be addressed, at Cancer Research Laboratory, 1303 N. Mission Road, Los Angeles, California 90033.

When used as drug carriers, anionic liposomes can reduce the chronic cardiac toxicity and increase the antileukemic activity of doxorubicin (DXN; Adriamycin). Continuing investigations, reported here, have now established the therapeutic benefits of this mode of drug delivery. Liposome encapsulation caused a prolonged elevation in DXN plasma levels and a 2-fold reduction in the exposure of cardiac tissue to the drug. This reduction, however, was not proportional to the substantial decrease in chronic heart toxicity observed in the earlier study. In vivo studies have demonstrated that the entrapped drug retains its full activity against Sarcoma 180 and significantly increases its action against Lewis lung carcinoma, as measured by reduced tumor volume. The increased antineoplastic activity was again not proportional to the increased association of drug with tumor tissue. The effect of liposome entrapment on the immune-suppressive activity of DXN was also examined to determine if factors other than the direct delivery of drug to tumor tissue might improve the therapeutic response. The suppression of the humoral immune response and peripheral leukocyte counts by free DXN was nearly abolished when the drug was administered in the liposome form. These experiments suggest that the improved therapeutic effect of encapsulation may be the outcome of three different mechanisms: (a) altered disposition into subcellular compartments, which reduces cardiotoxicity; (b) increased plasma drug exposure to tumor cells; and (c) significant reduction in the immune suppressive activity of DXN.

¹ Supported by a grant from the Weingart Foundation and by National Cancer Institute Fellowship Grant CA 06481. We are grateful to the Weingart Foundation for its generous support.

² Recipient of Public Health Services Grant CA 06481.

Received 1/ 4/82. Accepted 11/ 5/82.