ENHANCED TUMOR DELIVERY AND ANTITUMOR-ACTIVITY OF PALMITOYL RHIZOXIN USING STABLE LIPID EMULSIONS IN MICE

Purpose. A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes cons isting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, to xicities, and antitumor activities were evaluated after intravenous ad ministration to mice bearing subcutaneously inoculated M5076 sarcoma c ells. Methods, The levels of RS-1541 in the plasma and tissues includi ng tumor, were determined by HPLC. The maximum tolerated dose (MTD) wa s estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity. Results, There exi sted large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (refer ence solution), the small (110nm) and medium (230nm) size emulsions sh owed high concentrations of RS-1541 in the tumor, while the large emul sions (350nm-630nm) exhibited low concentrations. The MTD of RS-1541 w as reduced, when incorporated in the emulsions larger than 220nm in si ze. At MTD, each size of emulsions (70nm-380nm) effectively retarded t he tumor growth and increased survival time. The maximum effect was ac hieved for the 220 nm emulsions. Conclusions. When particle size is pr operly selected, these emulsions could be promising and effective as a n injectable carrier for lipophilic antitumor agents in order to enhan ce the tumor delivery and efficacies while reducing toxicities.