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Selective Delivery of Liposome-associated cis-Dichlorodiammineplatinum(II) by Heat and Its Influence on Tumor Drug Uptake and Growth¹

Institut für Medizin, Nuclear Research Center, KFA, D-5170 Jülich, West Germany [H. M., W. P., L. E. F.]; Human Oncology Department, University of Wisconsin, Madison, Wisconsin 53792 [M. B. Y.]; and Department of Theoretical Biology, National Cancer Institute, NIH, Bethesda, Maryland 20205 [J. N. W.]

In an attempt to optimize the chemotherapeutic treatment of mouse tumor Sarcoma 180, liposomes containing cis-dichlorodiammineplatinum(II) (PDD), having transition temperatures a few degrees higher than the rectal temperature of mice, were used in combination with local hyperthermia. The uptake of radioactive PDD by tumors heated for 1 hr at 42° was almost four-fold greater when the drug was associated in liposomes than if administered as free drug. Uptake of liposome-administered radioactive platinum by liver was twice that obtained with free PDD, whereas its incorporation by the kidney was the same by either method of drug administration.

The effect of various combinations of hyperthermia, drug-containing liposomes, and free PDD on tumor growth was also studied. Treatment with liposome-associated PDD plus local heating resulted in a dose-modifying factor of 7 when compared with free drug and no hyperthermia. The dose-modifying factor was 2.5 when PDD liposomes and heat were compared within free drug and heat. Thus, PDD could be specifically released from liposomes by heat and resulted in both a greater drug uptake and a delayed tumor growth following treatment. Potential normal tissue toxicity problems, however, still need to be resolved before clinical application of this combined modality will be possible.

¹ These studies were supported in part by NIH Grant GM-91846.

² To whom requests for reprints should be addressed.

Received 3/18/80. Accepted 1/22/81.

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