Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes
Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes
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DOI：
10.1016/j.jconrel.2005.04.003
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发表时间：
2005-07-20
影响因子：
10.8
通讯作者：
Kiwada, H
中科院分区：
文献类型：
--
作者：
Ishida, T;Harada, M;Kiwada, H
我们最近报道，第二剂量的聚乙二醇脂质体(m.w.2000)-修饰脂质体(mpeg(2000)-脂质体)在同一大鼠或小鼠体内以几天的间隔注射两次时，会迅速从血液中清除并在肝脏中蓄积(称为“加速血液清除(ABC)现象”)。在本研究中，我们观察到高剂量(5mU/kg)的常规脂质体(CL：没有聚乙二醇包被)可以引起同样的现象，而低剂量(0.001 mU/kg)的脂质体则不能。MPEG2000脂质体的诱导作用随首剂剂量的增加(0.001-5mU/kg)而降低。我们观察到初始注射的聚乙二醇脂质体的剂量和诱发ABC现象的程度之间存在着强烈的负相关关系：剂量越大，该现象越小。增加脂质体表面的聚乙二醇单甲氧基乙二醇酯的浓度超过5%会减弱而不是诱导这一现象的发生，但将聚乙二醇链的长度延长到分子量5000，则没有影响。在一系列的血液学、血清生化和组织病理学安全性评估中，我们在ABC现象的诱导过程中既没有观察到急性毒性，也没有观察到任何肝脏损害的迹象。透射电子显微镜对肝脏的形态观察显示，第二剂量的mpeg(2000)-脂质体在Kupffer细胞中广泛积聚，甚至在15min后也已积聚，这表明聚乙二醇脂质体不知何故已经失去了表面接枝的聚乙二醇脂质体对快速清除的保护作用。本文报道的观察结果可能会对用于多种药物治疗的聚乙二醇化脂质体制剂的设计和工程产生相当大的影响。(C)2005 Elsevier B.V.保留所有权利。
We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the "accelerated blood clearance (ABC) phenomenon"). In the present study we observed that a high dose (5 mu mol/kg) of conventional liposomes (CL: without a PEG-coating) can induce the same phenomenon, while a low lipid dose (0.001 mu mol/kg) did not. The induction of the phenomenon by mPEG2000-liposomes decreased with increasing first dose (0.001-5 mu mol/kg). We observed a strong inverse relationship between the dose of initially injected PEG(2000)-liposomes and the extent to which the ABC phenomenon was induced: the higher the dose the smaller the phenomenon. Increasing the PEG density at the liposome surface beyond 5 mol% attenuated rather than induced the induction of the phenomenon, but elongation of the PEG chain length up to M.W. 5000, had no effect. In a series of hematological, serum-biochemical and histopathological safety evaluations we observed neither acute toxicity nor any signs of hepatic damage during the induction of the ABC phenomenon. Morphological examination of the liver by transmission electron microscopy (TEM) showed extensive accumulation of the second dose of mPEG(2000)-liposomes in the Kupffer cells, even already after 15 min, suggesting that the PEG liposomes had somehow lost the protective effect of the surface-grafted PEG against rapid clearance. The observations reported in this paper may have a considerable impact on the design and engineering of PEGylated liposomal formulations for use in multiple drug therapy. (c) 2005 Elsevier B.V. All rights reserved.