AbstractIn order to avoid reticuloendothelial system (RES) uptake and prolong systemic circulation of cisplatin (CDDP)-encapsulating thermosensitive liposomes, stearylpolyoxyethylene (POE) derivatives [SnC, stearyl-O-(CH2CH22O)n-CH2COONa] were incorporated as membrane modifiers into lipid bilayers composed of dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC).The incorporation of S2C, S5C, S10C or S15C [lipid/SnC=10/2 (w/w)] greatly reduced liposomal aggregation without impairing liposomal stability. After being intravenously administered to rats, the liposomes remained longer in the systemic circulation and showed lower RES levels than the control liposomes. When incorporated into liposomes [DPPC/DSPC=7/3 (w/w)], S10C provided the greatest increase in systemic circulation time and the RES-avoiding activity among the modifiers tested. The systemic elimination rate (the ratio of the percent of the dose systemically eliminated to the AUC of the liposome level) for this type of liposome was 0.24/hr, about one fourth the rate for the control liposomes, and the RES uptake rate (the ratio of the percent of the dose taken up by the RES to the AUC) was 0.04/hr, one seventh the rate for the control liposomes. The RES uptake rate for S10C 7/3-liposomes was similar to the rate reported for GM1liposomes, although the systemic elimination rate was double that for the GM1liposomes.The obtained RES avoidance activity can be attributed to decreased liposomal aggregation and increased surface hydrophilicity. This type of thermosensitive liposome should be more useful in hyperthermia-mediated targeted tumor drug delivery systems than the thermosensitive liposomes without the modifiers to avoid RES uptake.