In vitro uptake and therapeutic application of liposome-encapsulated methotrexate in mouse hepatoma 129.

The biological activities of liposome-encapsulated and non-encapsulated methotrexate (MTX) were compared in vitro and in vivo using mouse Hepatoma 129 ascites tumor cells. Under in vitro conditions, cells accumulated up to 29% of [3H]-MTX when the drug was incorporated in the lipid bilayers of positively charged, unilamellar liposomes. There was no significant uptake of non-encapsulated MTX under the same conditions. A single intraperitoneal injection of liposome-encapsulated MTX (3 mg MTX/kg) increased the mean survival time of tumor-bearing mice to 42.5 +/- 11.2 days, compared to 23.5 +/- 2.2 days for untreated controls. Non-encapsulated MTX had no significant effect on survival time. Thus the in vivo treatment studies appear to agree with the in vitro uptake measurements. Addition of galactolipids to the lipid bilayers of liposomes did not increase in vitro uptake of encapsulated MTX and gave no additional improvement in therapeutic effectiveness. Encapsulation of MTX in liposomes might thus be used to increase uptake of the drug in cells which may be deficient in MTX transport.