MEMBRANE MODIFICATION BY NEGATIVELY CHARGED STEARYLPOLYOXYETHYLENE DERIVATIVES FOR THERMOSENSITIVE LIPOSOMES - REDUCED LIPOSOMAL AGGREGATION AND AVOIDANCE OF RETICULOENDOTHELIAL SYSTEM UPTAKE

In order to avoid reticuloendothelial system (RES) uptake and prolong systemic circulation of cisplatin (CDDP)-encapsulating thermosensitive liposomes, stearylpolyoxyethylene (POE) derivatives [SnC, stearyl-O-( CH2CH2O)n-CH2COONa] were incorporated as membrane modifiers into lipid bilayers composed of dipalmitoylphosphatidylcholine (DPPC) and distea roylphosphatidylcholine (DSPC). The incorporation of S2C, S5C, S10C or S15C [lipid/SnC=10/2 (w/w)] greatly reduced liposomal aggregation wit hout impairing liposomal stability. After being intravenously administ ered to rats, the liposomes remained longer in the systemic circulatio n and showed lower RES levels than the control liposomes. When incorpo rated into liposomes [DPPC/DSPC=7/3 (w/w)], S10C provided the greatest increase in systemic circulation time and the RES-avoiding activity a mong the modifiers tested. The systemic elimination rate (the ratio of the percent of the dose systemically eliminated to the AUC of the lip osome level) for this type of liposome was 0.24/hr, about one fourth t he 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 GM(1) lipo somes, although the systemic elimination rate was double that for the GM(1) liposomes. The obtained RES avoidance activity can be attributed to decreased liposomal aggregation and increased surface hydrophilici ty. This type of thermosensitive liposome should be more useful in hyp erthermia-mediated targeted tumor drug delivery systems than the therm osensitive liposomes without the modifiers to avoid RES uptake.