LIPOSOME DISPOSITION INVIVO .3. DOSE AND VESICLE-SIZE EFFECTS
LIPOSOME DISPOSITION INVIVO .3. DOSE AND VESICLE-SIZE EFFECTS
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DOI：
10.1016/0005-2760(81)90311-8
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发表时间：
1981-01-01
期刊：
影响因子：
--
通讯作者：
HUNT, CA
中科院分区：
文献类型：
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作者：
ABRA, RM;HUNT, CA
脂质剂量（4.3 ~ 512.8 .mu）的影响。在体内研究了包封放射性菊粉的脂质体（Mol total脂/kg body wt）对小鼠脏器结合和/或吸收放射性标签能力的影响。研究了三种不同的脂质体直径：0.46 μ。m (L), 0.16 .mu。m (m)和0.058 .mu。m (S)。所有脂质体均带磷脂酰胆碱/磷脂酸/胆固醇/ α的脂质组成负电荷。-生育酚的摩尔比为4:1:5:0.1或4:1:1:0.05。2小时后，放射性标记的总体分布与主要在res中的定位一致。三种尺寸的肝脏都随着脂质剂量的增加而饱和，同时血液水平也相应增加。脾脏放射性随L-脂质体和m -脂质体剂量的增加而升高，随s -脂质体剂量的增加而降低。残留胴体中的水平没有变化趋势。通过调节脂质体脂质剂量和囊泡直径，给药剂量在血液中的百分比可变化733倍，在脾脏中的百分比可变化9倍，在肝脏中的百分比可变化4倍。体内稳定性排名为L > M > s脂质体。对体内稳定性差异的校正减少了3种脂质体大小之间器官积累的差异。器官积累模式提示脂质体配置的剂量和直径依赖机制。预计当固定脂质体组合物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。重新绘制肝脏和脾脏的剂量值百分比与给药脂质体的数量，揭示了L-、M-和s -脂质体的饱和模式，每种情况下都有所不同。将数据与剂量的总表面积进行对比，揭示了肝脏中L-、M-和s -脂质体以及脾脏中L-和M-脂质体的相似分布模式。除组成外，脂质剂量、总脂质体表面积和有效平均直径也是重要的药代动力学变量。通过脂质体给药的囊化剂或靶组织的治疗指数的优化将需要考虑脂质体剂量的表面积和直径以及脂质体组合物。
The effect of lipid dose (4.3-512.8 .mu.mol total lipid/kg body wt), administered i.v. as liposomes encapsulating radioactive inulin, upon the ability of mouse organs to bind and/or take-up the radioactive label was studied in vivo. Three different liposome diameters were investigated: 0.46 .mu.m (L), 0.16 .mu.m (M) and 0.058 .mu.m (S). All liposomes were negatively charged with a lipid composition of phosphatidylcholine/phosphatidic acid/cholesterol/.alpha.-tocopherol in the molar ratio 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 RES. A saturation of liver with increasing lipid dose was demonstrated for all 3 sizes, together with a corresponding increase in blood levels. Spleen radioactivity increased with increasing dose of L- and M-liposomes, but decreased for increasing dose of S-liposomes. Levels in residual carcass exhibited no trend. 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 and liver 4-fold. Stability in vivo was ranked L > M > S-liposomes. Correction for differences of in vivo stability reduced the differences in organ accumulation between the 3 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. Re-plotting the percent dose values for liver and spleen vs. the number of liposomes administered revealed a saturation pattern for L-, M- and S-liposomes which differed in each case. Plotting the data vs. 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. In addition to composition, the lipid dose, total liposomal surface area and effective mean diameter are important pharmacokinetic variables. 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.