Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice.
Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice.
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DOI：
10.1016/j.jconrel.2003.12.011
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发表时间：
2004-03
期刊：
影响因子：
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通讯作者：
T. Ishida;Takako Ichikawa;M. Ichihara;Y. Sadzuka;H. Kiwada
中科院分区：
文献类型：
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作者：
T. Ishida;Takako Ichikawa;M. Ichihara;Y. Sadzuka;H. Kiwada
使用小鼠作为模型，我们最近报道了聚乙二醇（PEG）（M.W. 2000)-修饰的脂质体（mPEG 2000-脂质体）在以一定间隔静脉内注射时消失[称为“加速血液清除（ABC）现象”]。在此，我们报告了一项研究的问题，无论是物理化学性质的前剂量的脂质体，如聚乙二醇化程度，PEG链长，脂质剂量，表面电荷，大小，发挥作用，诱导这种现象。注射常规脂质体（无PEG涂层）显著诱导了该现象。常规脂质体的PEG化随着PEG衍生物的摩尔含量和PEG链长度的增加而稍微减弱了该现象的诱导。这些发现清楚地表明，脂质体的聚乙二醇化并不是ABC现象的主要原因，而是在预防ABC现象方面发挥了作用。此外，增加前一剂量mPEG 2000-脂质体（0-25 μmol/kg）中的脂质剂量会增加ABC现象的诱导。以S形方式。脂质体的表面电荷和大小对于诱导该现象并不关键，尽管通常这些作为脂质体的生物分布的决定因素。本文报告的结果清楚地表明，先前剂量的脂质体的理化性质强烈影响随后注射mPEG 2000-脂质体的药代动力学行为：PEG化程度和脂质剂量有影响，但表面电荷和大小没有影响。本文报道的结果对用于多种药物治疗以及涉及使用脂质体药物的治疗的脂质体制剂的设计和工程化具有相当大的影响。
Using mice as a model, we recently reported that the long-circulating properties of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) disappeared when they were intravenously injected at certain intervals [referred to as the “accelerated blood clearance (ABC) phenomenon”]. Herein, we report on a study of issue of whether physicochemical properties of a prior dose of liposomes such as degree of PEGylation, PEG chain length, lipid dose, surface charge, size, play a role in inducing this phenomenon. The injection of conventional liposomes (without a PEG-coating) significantly induced the phenomenon. The PEGylation of conventional liposomes attenuated the induction of the phenomenon somewhat with increasing molar content of PEG derivative and PEG chain length. These findings clearly suggest that the PEGylation of liposomes are not the major cause of the ABC phenomenon but, rather, played a role in preventing it. In addition, increasing the lipid dose in a prior dose of mPEG2000-liposomes (0–25 μmol/kg) increased the induction of the phenomenon in a sigmoid manner. The surface charge and size of the liposomes were not critical for the induction of the phenomenon, although generally these serve as determinants in the biodistribution of liposomes. The results reported here clearly indicate that the physicochemical properties of a prior dose of liposomes strongly affect the pharmacokinetic behavior of a subsequent injection of mPEG2000-liposomes: The extent of PEGylation and the lipid dose had an effect, but the surface charge and size did not. The results reported herein have a considerable impact on the design and engineering of liposomal formulations for use in multiple drug therapy as well as in therapy that involves the use of liposomal drugs.