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 degrees 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.