Enhanced Therapeutic Effect against Liver W256 Carcinosarcoma with Temperature-sensitive Liposomal Adriamycin Administered into the Hepatic Artery

The antitumor activity of Adriamycin encapsulated in temperature-sensitive liposomes combined with local hyperthermia (HT) was tested in rats bearing well-developed liver W256 carcinosarcoma tumors. Two h after rats received Adriamycin encapsulated in temperature-sensitive liposomes via either the hepatic artery (i.a.) or the femoral vein (i.v.) or free Adriamycin i.a., liver HT was applied at 42°C for 6 min. In animals treated with liposomal Adriamycin i.a., HT resulted in a 38% reduction in the tumor volume ratio and a 2.2-fold increase in the life span of the animals. In animals treated with liposomal Adriamycin i.v. or free Adriamycin i.a., HT did not alter the tumor volume ratio or life span of the animals. Administration i.a. of liposomal Adriamycin markedly increased the tumor drug levels (4-14-fold), reduced the systemic distribution of the drug, and slowed the drug decrease from both the tumor and liver compared with animals treated i.v. Liver HT in animals treated with liposomal Adriamycin i.a. further increased tumor drug levels by 1.5-2.6-fold, further slowed the drug decrease from the tumor, and resulted in a dissociation of the parallel decrease of drug and lipid from the tumor. This latter effect was not observed in the other groups. These pharmacological findings combined with the lack of beneficial effect from HT in animals treated with free Adriamycin i.a. or liposomal Adriamycin i.v. suggest that i.a. administration of Adriamycin encapsulated in temperature-sensitive liposomes results in a significant retention of intact liposomes in the tumor vasculature that are able to release the encapsulated drug into the tumor cell compartment upon raising the temperature to the phase transition level.