Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models.
We investigated the pharmacokinetics and therapeutic efficacy of cisplatin encapsulated in polyethyleneglycol-coated long-circulating liposomes in a formulation referred to as SPI-077, in three mouse tumor models (M-109 lung carcinoma inoculated s.c., J-6456 lymphoma inoculated i.p. and A-375 melanoma inoculated s.c.). Tumor-bearing mice were injected i.v. with single doses of SPI-077 and cisplatin. For pharmacokinetic experiments, mice were sacrificed at different timepoints post-treatment. Platinum levels were determined in plasma, spleen, liver, kidneys and tumors using flameless atomic absorption spectrophotometry. Survival times and/or tumor size were recorded for therapeutic studies. The pharmacokinetic studies revealed a prolonged circulation time and enhanced tumor uptake for SPI-077. In contrast to these results, no superior antitumor activity of SPI-077 over cisplatin could be observed in all tumor models. In vitro release experiments showed a negligible release (below 10%) of platinum from the liposomes. An in vitro cytotoxicity assay indicated a reduced cytotoxic activity of SPI-077 in comparison to cisplatin. We concluded that SPI-077 is being delivered to the tumor sites in a low bioavailability form, with extremely slow release kinetics. This explains the discrepant results of high platinum concentrations in tumors and reduced therapeutic activity after administration of SPI-077.
Bandak
S
S
Sharet Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Goren
D
D
Horowitz
A
A
Tzemach
D
D
Gabizon
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D015996:Survival Rate; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D002945:Cisplatin