Kurihara A, Shibayama Y, Mizota A, Yasuno A, Ikeda M, Sasagawa K, Kobayashi T, Hisaoka M
Product Development Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Pharm Res. 1996 Feb;13(2):305-10. doi: 10.1023/a:1016063719541.
A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells.
The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity.
There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm-630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm-380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions.
When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.
将一种高度亲脂性抗肿瘤药物13 - O - 棕榈酰根霉素（RS - 1541）掺入由甘油三酯ODO和表面活性剂HCO - 60组成的各种大小的脂质乳剂中。对皮下接种M5076肉瘤细胞的小鼠静脉给药后，评估其药代动力学、毒性和抗肿瘤活性。
通过高效液相色谱法测定血浆和包括肿瘤在内的组织中RS - 1541的水平。通过毒性死亡和体重变化估计最大耐受剂量（MTD）。测量肿瘤直径的减小以评估抗肿瘤活性。
RS - 1541的药代动力学存在很大差异，这取决于乳剂颗粒的大小。与胶体溶液（参比溶液）相比，小（110nm）和中（230nm）尺寸的乳剂在肿瘤中显示出高浓度的RS - 1541，而大乳剂（350nm - 630nm）则表现出低浓度。当RS - 1541掺入尺寸大于220nm的乳剂中时，其MTD降低。在MTD时，每种尺寸的乳剂（70nm - 380nm）均有效抑制肿瘤生长并延长存活时间。220nm乳剂达到了最大效果。
如果能适当选择粒径，这些乳剂有望成为亲脂性抗肿瘤药物的有效注射载体，以增强肿瘤递送和疗效，同时降低毒性。
