Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor.
Tumor drug uptake and antitumor efficacy of free and liposomal doxorubicin (DOX) were determined in the SC115 Shionogi mouse mammary tumor. Liposomal DOX systems were prepared by pH gradient-driven drug encapsulation in 170 nm egg phosphatidylcholine/cholesterol (55:45, mol ratio) vesicles. Intravenous injection of free DOX at 6.5 mg/kg, the maximum tolerated dose for free drug in the multiple dose therapy regimen, resulted in tumor-associated drug levels of 2.0 micrograms/g tissue at 1 h which remained constant over 24 h. Liposomal DOX injected at 6.5 mg/kg led to an accumulation of drug in the tumor from 2.6 micrograms/g tissue to 5.5 micrograms/g tissue between 1 h and 24 h, respectively. Increasing the dose of liposomal DOX to 13.0 mg/kg increased tumor drug uptake levels to 5.7 micrograms/g and 10.2 micrograms/g tissue at 1 h and 24 h, respectively. Administration of free or liposome encapsulated DOX every 7 days for 3 weeks resulted in a dose-dependent decrease in tumor growth rate. However, liposomal DOX injected at 6.5 mg/kg exhibited enhanced tumor growth inhibition compared to an equivalent dose of free drug. Further, the ability to administer increased doses of the less toxic liposomal DOX not only resulted in a greater inhibition of tumor growth but also significantly reduced tumor weight. Tumors weighing as much as 5 g were diminished to less than 0.5 g upon treatment with liposomal DOX at a dose of 13 mg/kg. In addition, groups receiving the highest liposomal DOX dose exhibited 25% complete tumor regression which persisted over the 50-day study period. These results demonstrate the ability of appropriately designed liposomal DOX systems to significantly enhance the delivery and retention of drug at solid tumor sites, resulting in increased therapeutic activity.
Mayer
L D
LD
Department of Biochemistry, University of British Columbia, Vancouver, Canada.
Bally
M B
MB
Cullis
P R
PR
Wilson
S L
SL
Emerman
J T
JT
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice
D008081:Liposomes; D004317:Doxorubicin