MEMBRANE MODIFICATION BY NEGATIVELY CHARGED STEARYLPOLYOXYETHYLENE DERIVATIVES FOR THERMOSENSITIVE LIPOSOMES - REDUCED LIPOSOMAL AGGREGATION AND AVOIDANCE OF RETICULOENDOTHELIAL SYSTEM UPTAKE
K. Iga et al., MEMBRANE MODIFICATION BY NEGATIVELY CHARGED STEARYLPOLYOXYETHYLENE DERIVATIVES FOR THERMOSENSITIVE LIPOSOMES - REDUCED LIPOSOMAL AGGREGATION AND AVOIDANCE OF RETICULOENDOTHELIAL SYSTEM UPTAKE, Journal of drug targeting., 2(3), 1994, pp. 259-267
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.