Abra R M, Hunt C A
Biochim Biophys Acta. 1981 Dec 23;666(3):493-503. doi: 10.1016/0005-2760(81)90311-8.
The effect of lipid dose (4,3-512.8 mumol total lipid/kg body weight), administered intravenously as liposomes encapsulating radioactive inulin, upon the ability of mouse organs to bind and/or take-up the radioactive label has been studied in vivo. Three different liposome diameters were investigated: 0.46 micrometers (L), 0.16 micrometers (M) and 0.058 micrometers(S). All liposomes were negatively charged with lipid composition of phosphatidylcholine/phosphatidic acid/cholesterol/alpha-tocopherol in the molar ration 4 : 1 : 5 : 0.1 or 4 : 1 : 1 : 0.05. Overall radioactive label disposition after 2 h was consistent with localization predominantly in the reticuloendothelial system. A saturation of liver with increasing lipid dose was demonstrated for all three sizes, together with a corresponding increase in blood levels. Spleen radioactivity increased with increasing dose of L- and M-liposomes, but decreased for increasing doses of S-liposomes. Levels in residual carcass exhibited no trend. It was noted that by adjusting liposomal lipid dose and vesicle diameter the percentage of administered dose present in blood could be varied 733-fold, that in spleen 9-fold, liver 4-fold. Stability in vivo was ranked L greater than M greater than S-liposomes. Correction for differences of in vivo stability reduced the differences in organ accumulation between the three liposome sizes. The organ accumulation pattern suggested a dose- and diameter-dependent mechanism for liposome disposition. It was expected that when doses of fixed liposome composition were expressed as number of liposomes or their total surface area, organ saturation patterns would be similar. However, re-plotting the percent dose values for liver and spleen versus the number of liposomes administered revealed a saturation pattern for L-, M- and S-liposomes which was different in each case. Plotting the data versus the total surface area of the dose revealed a similar disposition pattern for L-, M- and S-liposomes in liver and L- and M-liposomes in spleen. The data indicate that in addition to composition, the lipid dose, total liposomal surface area and effective mean diameter are important pharmacokinetic variables. Further, the optimization of the therapeutic index of an encapsulated agent or target-tissue delivery via liposomes will require consideration of both the surface area and diameter of the liposome doses together with liposome composition.
通过静脉注射包裹放射性菊粉的脂质体给予脂质剂量（总脂质4.3 - 512.8 μmol/kg体重），研究其对小鼠器官结合和/或摄取放射性标记物能力的体内影响。研究了三种不同的脂质体直径：0.46微米（L）、0.16微米（M）和0.058微米（S）。所有脂质体均带负电荷，脂质组成是磷脂酰胆碱/磷脂酸/胆固醇/α-生育酚，摩尔比为4 : 1 : 5 : 0.1或4 : 1 : 1 : 0.05。2小时后总的放射性标记物分布情况与主要定位于网状内皮系统一致。对于所有三种大小的脂质体，均显示随着脂质剂量增加肝脏出现饱和现象，同时血液水平相应升高。L型和M型脂质体的脾脏放射性随剂量增加而增加，但S型脂质体的脾脏放射性随剂量增加而降低。残留胴体中的水平无明显趋势。值得注意的是，通过调整脂质体脂质剂量和囊泡直径，血液中给药剂量的百分比可在733倍范围内变化，脾脏中为9倍，肝脏中为4倍。体内稳定性排序为L型脂质体＞M型脂质体＞S型脂质体。校正体内稳定性差异后，三种脂质体大小之间的器官蓄积差异减小。器官蓄积模式提示脂质体分布存在剂量和直径依赖性机制。预计当固定脂质体组成的剂量以脂质体数量或其总表面积表示时，器官饱和模式将相似。然而，重新绘制肝脏和脾脏的剂量百分比值与给药脂质体数量的关系图，显示L型、M型和S型脂质体的饱和模式在每种情况下均不同。将数据绘制为剂量总表面积的函数图，显示L型、M型和S型脂质体在肝脏中的分布模式相似，L型和M型脂质体在脾脏中的分布模式相似。数据表明，除组成外，脂质剂量、脂质体总表面积和有效平均直径都是重要的药代动力学变量。此外，通过脂质体优化包封剂的治疗指数或靶向组织递送将需要同时考虑脂质体剂量的表面积和直径以及脂质体组成。
