We have investigated the tissue distribution, toxicity, and antitumor activity of anthracyclines encapsulated in hydrogenated phosphatidyl-inositol (HPI)-containing liposomes which show a characteristic long circulation time in plasma (J. Natl. Cancer Inst., 81: 1484–1488, 1989). Phosphatidylglycerol (PG)-containing liposomes were used for comparison. Doxorubicin (DOX) or epirubicin (EPI) was encapsulated in the aqueous interior of small (65–100 nm mean diameter) HPI or PG liposomes. The DOX and EPI levels in i.m. tumor implants of the J6456 lymphoma were significantly raised by delivery in HPI liposomes but not by delivery in PG liposomes. No such increase was observed in normal muscle tissue. When DOX encapsulated in HPI liposomes was injected i.v. into BALB/c mice bearing an ascitic form of the J6456 lymphoma, more than 10% of the injected dose was recovered in the ascitic fluid in liposome-associated form. No significant accumulation of liposomal drug was observed in peritoneal washes from tumor-free mice. DOX encapsulation in either PG- or HPI-containing liposomes reduced the lethal toxicity of the drug in mice. However, only the HPI-DOX formulation was significantly more active than free DOX in the treatment of the ascitic J6456 tumor at all dose levels tested. Therapeutic results with EPI encapsulated in HPI liposomes also showed an efficacy superior to that of free EPI. These studies provide evidence that anthracyclines delivered in long-circulating liposomes extravasate with relative selectivity in tumor areas, improving the overall therapeutic index.

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This study was supported by Liposome Technology, Inc. (Menlo Park, CA), and by a Research Career Development Award from the Israel Cancer Research Fund.

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