Four types of
lipid emulsion for highly lipophilic antitumour agent
RS-1541 (13-O-palmitoylrhizoxin) with mean particle diameters of 200-260 nm were prepared using
soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and
lecithin (LEC) or polyoxyethylene-(60)-hydrogenated
castor oil (HCO-60) for
surfactants. The lipolysis rate of HCO-60-emulsified
emulsions by
lipoprotein lipase was much slower than that of LEC-emulsified
emulsions. Particle sizes of
emulsions incubated in plasma with the
lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/
HCO-60, and ODO/
HCO-60 emulsions, respectively, showing an apparent size decrease for LEC-emulsified
emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC
emulsions of
RS-1541 in the reticuloendothelial system (RES) were 81.2 and 135.3 mL h(-1), respectively, and AUC values were 4.0 and 1.3 microg h mL(-1), respectively. In contrast, RES uptake clearances of HCO-60
emulsions of
RS-1541 were considerably lower (4.2 mL h(-1) for SOY/
HCO-60; 2.2 mL h(-1) for ODO/
HCO-60), resulting in high AUC values (35.4 microg h mL(-1) for SOY/
HCO-60; 63.9 microg h mL(-1) for ODO/
HCO-60). The concentrations of
RS-1541 in tumour tissues after an
intravenous administration of ODO/
HCO-60 emulsions of
RS-1541 to mice bearing solid tumour M5076
sarcoma were about ten times higher than those after the administration of SOY/LEC
emulsions. These results indicate that HCO-60
emulsions, compared with conventional LEC
emulsions, are more stable to
lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized
emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the
drug delivery in tumours.