Storm G, Roerdink F H, Steerenberg P A, de Jong W H, Crommelin D J
Cancer Res. 1987 Jul 1;47(13):3366-72.
The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-containing liposomes was studied in immunoglobulin solid immunocytoma-bearing Lou/M Wsl rats. Rats bearing a tumor with a diameter between 20 and 30 mm were treated i.v. with 2 mg/kg free DXR or different DXR-containing liposome types for 5 consecutive days followed by one injection more at day 11 after start of therapy. A similar pattern of tumor regression was observed for free DXR and DXR entrapped in "fluid" liposome types. However, DXR entrapped in "solid" liposome types expressed an antitumor activity which was significantly delayed; during the first 3 days after start of therapy solid DXR-containing liposomes were less effective in inducing antitumor activity than fluid DXR-containing liposomes. In order to gain more insight into the mode of action of DXR-containing liposomes, one of the solid liposome types [composed of distearoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and cholesterol (chol)] was compared with one of the fluid liposome types [composed of egg phosphatidylcholine, phosphatidylserine, and chol] with respect to distribution and integrity in vivo. Results obtained after i.v. administration of [3H]inulin-labeled vesicles to tumor-bearing animals suggested that a differential liposome uptake by the tumor was not relevant for the explanation of the delayed antitumor effect. To monitor the structural integrity of liposomes after i.v. injection, the liposomes were double radiolabeled with [3H]inulin as a marker of the aqueous phase and cholesteryl [14C]oleate as a marker of the lipid phase. The bilayer structure of both liposome types remained intact during their presence in the blood compartment. Intact liposomes were taken up primarily by liver and spleen with subsequent degradation of the liposome structure. The degradation rate appeared to be dependent on the lipid composition of the liposomal membranes; phosphatidylcholine/phosphatidylserine/chol liposomes were degraded much faster than distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol/chol liposomes. The difference in degradation rate was manifested more clearly in the spleen than in the liver. In vitro investigations on uptake and processing of liposomes by liver macrophages indicated that the difference in degradation rate between liver and spleen was caused by intrahepatic reutilization of [14C]oleate liberated from the liposome structures.(ABSTRACT TRUNCATED AT 400 WORDS)
在携带免疫球蛋白实体免疫细胞瘤的Lou/M Wsl大鼠中，研究了脂质组成变化对含阿霉素（DXR）脂质体抗肿瘤活性的影响。对肿瘤直径在20至30毫米之间的大鼠静脉注射2毫克/千克游离DXR或不同类型的含DXR脂质体，连续5天，然后在治疗开始后第11天再注射一次。游离DXR和包封在“流体”型脂质体中的DXR观察到相似的肿瘤消退模式。然而，包封在“固体”型脂质体中的DXR表现出明显延迟的抗肿瘤活性；在治疗开始后的前3天，含固体DXR的脂质体在诱导抗肿瘤活性方面比含流体DXR的脂质体效果差。为了更深入了解含DXR脂质体的作用方式，将其中一种固体脂质体类型[由二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰甘油和胆固醇（chol）组成]与一种流体脂质体类型[由蛋黄卵磷脂、磷脂酰丝氨酸和chol组成]在体内的分布和完整性方面进行了比较。对荷瘤动物静脉注射[3H]菊粉标记的脂质体后获得的结果表明，肿瘤对脂质体的不同摄取与延迟抗肿瘤作用的解释无关。为了监测静脉注射后脂质体的结构完整性，脂质体用[3H]菊粉作为水相标记物和胆固醇[14C]油酸酯作为脂质相标记物进行双重放射性标记。两种脂质体类型的双层结构在血液中时保持完整。完整的脂质体主要被肝脏和脾脏摄取，随后脂质体结构降解。降解速率似乎取决于脂质体膜的脂质组成；卵磷脂/磷脂酰丝氨酸/chol脂质体的降解速度比二硬脂酰磷脂酰胆碱/二棕榈酰磷脂酰甘油/chol脂质体快得多。降解速率的差异在脾脏中比在肝脏中表现得更明显。对肝脏巨噬细胞摄取和处理脂质体的体外研究表明，肝脏和脾脏之间降解速率的差异是由从脂质体结构中释放的[14C]油酸在肝内的再利用引起的。（摘要截短于400字）
