title: Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes.
abstract: 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 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 diameter. Topical hyperthermia treatment consisting of 42 degrees C minimum 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 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.
authors.affiliation: Cancer Research Institute, University of California, San Francisco 94143.
authors.forename: S K
authors.initials: SK
authors.lastname: Huang
authors.forename: P R
authors.initials: PR
authors.lastname: Stauffer
authors.forename: K
authors.initials: K
authors.lastname: Hong
authors.forename: J W
authors.initials: JW
authors.lastname: Guo
authors.forename: T L
authors.initials: TL
authors.lastname: Phillips
authors.forename: A
authors.initials: A
authors.lastname: Huang
authors.forename: D
authors.initials: D
authors.lastname: Papahadjopoulos
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D004337:Drug Carriers; D005260:Female; D006979:Hyperthermia, Induced; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D013997:Time Factors
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin