LIPOSOMES AND HYPERTHERMIA IN MICE - INCREASED TUMOR UPTAKE AND THERAPEUTIC EFFICACY OF DOXORUBICIN IN STERICALLY STABILIZED LIPOSOMES

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 temperature s with 50% bovine serum, approximately 20% of the encapsulated DOX was released at 42 degrees C within 1 min, compared with less than 1% DOX released at 37 degrees C. In vivo, mice were implanted s.c. with C-26 colon carcinoma in both flanks to produce matched tumors 6-10 mm in d iameter. Topical hyperthermia treatment consisting of 42 degrees C min imum tumor temperature for 30 min was applied with a microwave device to the tumor on one side only at 1 h after i.v. injection of SL-DOX or free DOX. Tumor DOX concentration in the group which was given inject ions of SL-DOX and sacrificed 2 h after drug injection was 1.5-fold hi gher compared with the nonheated tumor in mice given injections of SL- DOX. At 24 h after injection the thermal enhancement ratio for DOX acc umulation in tumor remained at 1.5. In addition, there was a 15-fold h igher concentration of DOX in tumor from the group given injections of SL-DOX compared to mice given injections of free doxorubicin. To asse ss 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-D OX. 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 hy perthermia, and 59% compared to those receiving two hyperthermia treat ments but with free DOX. A single hyperthermia treatment either at 1 o r 24 h was less effective in increasing life span compared with two tr eatments, but all groups treated with SL-DOX and single hyperthermia w ere still superior to the control groups, showing a 27-38% increase in life span.