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Liposomes and Hyperthermia in Mice: Increased Tumor Uptake and Therapeutic Efficacy of Doxorubicin in Sterically Stabilized Liposomes¹

Cancer Research Institute [S. K. H., K. H., J. W. H. G., D. P.], Radiation Oncology [P. R. S., T. L. P.], University of California, San Francisco, 94143, and Liposome Technology, Inc., Menlo Park [A. H.], California 94025

We have shown that sterically stabilized (Stealth) liposomes (SL), can accumulate in the extracellular space within tumors, and may improve pharmacokinetics and therapeutic efficacy of encapsulated doxorubicin (SL-DOX). When SL-DOX were incubated in vitro at different temperatures with 50% bovine serum, approximately 20% of the encapsulated DOX was released at 42°C within 1 min, compared with less than 1% DOX released at 37°C. In vivo, mice were implanted s.c. with C-26 colon carcinoma in both flanks to produce matched tumors 6–10 mm in diameter. Topical hyperthermia treatment consisting of 42°C minimum tumor temperature for 30 min was applied with a microwave device to the tumor on one side only at 1 h after l.v. injection of SL-DOX or free DOX. Tumor DOX concentration in the group which was given injections of SL-DOX and sacrificed 2 h after drug injection was 1.5-fold higher compared with the nonheated tumor in mice given injections of SL-DOX. At 24 h after injection the thermal enhancement ratio for DOX accumulation in tumor remained at 1.5. In addition, there was a 15-fold higher concentration of DOX in tumor from the group given injections of SL-DOX compared to mice given injections of free doxorubicin. To assess therapeutic efficacy, we treated mice with hyperthermia for 15 min either at 1, or at 24 h or at both time points after injection of SL-DOX. We have found that the life span of the group of mice treated with SL-DOX and two 15-min hyperthermia treatments increased 51% compared with control groups receiving the same dosage of SL-DOX but without hyperthermia, and 59% compared to those receiving two hyperthermia treatments but with free DOX. A single hyperthermia treatment either at 1 or 24 h was less effective in increasing life span compared with two treatments, but all groups treated with SL-DOX and single hyperthermia were still superior to the control groups, showing a 27–38% increase in life span.

¹ This work was supported by grants from Liposome Technology, Inc., and Yen Microlithography.

² To whom requests for reprints should be addressed, at Liposome Technology, Inc., 1050 Hamilton Court, Menlo Park, CA 94025.

Received 10/ 1/93. Accepted 2/18/94.

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