Kurihara A, Shibayama Y, Mizota A, Yasuno A, Ikeda M, Sasagawa K, Kobayashi T, Hisaoka M
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Biopharm Drug Dispos. 1996 May;17(4):331-42. doi: 10.1002/(SICI)1099-081X(199605)17:4<331::AID-BDD959>3.0.CO;2-B.
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.
使用大豆油（SOY）或二辛酰癸酰甘油（ODO）作为油相，卵磷脂（LEC）或聚氧乙烯（60）氢化蓖麻油（HCO - 60）作为表面活性剂，制备了四种平均粒径为200 - 260 nm的用于高亲脂性抗肿瘤药物RS - 1541（13 - O - 棕榈酰根霉素）的脂质乳剂。脂蛋白脂肪酶对HCO - 60乳化的乳剂的脂解速率比LEC乳化的乳剂慢得多。在血浆中与脂肪酶一起孵育6小时的乳剂的粒径分别为SOY/LEC、ODO/LEC、SOY/HCO - 60和ODO/HCO - 60乳剂初始值的75%、79%、101%和93%，表明LEC乳化的乳剂粒径明显减小。在大鼠中，RS - 1541的SOY/LEC和ODO/LEC乳剂在网状内皮系统（RES）中的摄取清除率分别为81.2和135.3 mL h⁻¹，AUC值分别为4.0和1.3 μg h mL⁻¹。相比之下，RS - 1541的HCO - 60乳剂在RES中的摄取清除率显著更低（SOY/HCO - 60为4.2 mL h⁻¹；ODO/HCO - 60为2.2 mL h⁻¹），导致AUC值较高（SOY/HCO - 60为35.4 μg h mL⁻¹；ODO/HCO - 60为63.9 μg h mL⁻¹）。给患有实体瘤M5076肉瘤的小鼠静脉注射RS - 1541的ODO/HCO - 60乳剂后，肿瘤组织中RS - 1541的浓度比注射SOY/LEC乳剂后高约十倍。这些结果表明，与传统的LEC乳剂相比，HCO - 60乳剂对脂蛋白脂肪酶更稳定，在RES器官中的摄取较低，在血浆中循环时间长，在肿瘤中的分布高。因此，这些空间稳定的乳剂可能作为高亲脂性抗肿瘤药物的有效载体，以增强药物在肿瘤中的递送。
