Effect of Vesicle Size on the Clearance,Distribution,and Tumor Uptake of Temperature-Sensitive Liposomes

The blood clearance, tissue distribution, and tumor uptake of temperaturesensitive liposomes containing the anticancer drug cytosine [³H]-1-β-D-arabinofuranoside (Ara-C) or [³H]-methotrexate (MTX) were measured. Large unilamellar liposomes composed of a mixture of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (4:1 by weight) were formed by reverse-phase evaporation and sequentially extruded through polycarbonate membranes with pore sizes of 0.4, 0.2, 0.1, 0.08, and 0.05 μm. The liposomes were injected intravenously via the tail vein into B6D2F1 mice containing solid tumors (M5076 ovarian carcinoma) implanted in both hind feet. Drug release, organ distribution, and tumor uptake were studied during and following local hyperthermia treatments (42°C, 60 minutes). Local hyperthermia increased the relative amount of liposome encapsulated drug delivered to a heated solid tumor compared with the unheated control. The clearance studies showed that liposome blood clearance was inversely proportional to liposome size. However, tumor uptake was not significantly affected by reducing liposome size. In addition, for the range of liposome sizes studied, the majority of the liposome encapsulated drug was found in the liver, spleen, and kidney; not in the heated tumor.