Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression
Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression
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DOI：
10.1016/j.bbamem.2005.02.001
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发表时间：
2005-05-20
影响因子：
3.4
通讯作者：
MacLachlan, I
中科院分区：
文献类型：
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作者：
Ambegia, E;Ansell, S;MacLachlan, I
稳定的质粒脂质颗粒（SPLP）由被脂质双层包围的单拷贝DNA组成，颗粒小（类似于100 nm）、稳定、单分散并且具有低表面电荷。附着在脂质锚上的可扩散聚乙二醇（PEG）涂层对SPLP的功能至关重要。PEG-脂质以由脂质锚的大小确定的速率交换出双层。在这里，我们表明，SPLP可以使用一系列的PEG-二酰基甘油脂质（PEG-S-DAGs）制备。掺入PEG-二肉豆蔻酰甘油（C-14）、PEG-二棕榈酰甘油（C-16）或PEG-二硬脂酰甘油（C-18）制备SPLP，并使用FRET测定法测定PEG-脂质从双层扩散的速率。SPLP药代动力学证实了PEG-脂质组分的稳定性与循环寿命之间的相关性。具有较长脂质锚的PEG-S-DAG产生具有较长循环半衰期的更稳定的SPLP颗粒，从而产生肿瘤递送和基因表达的增加。含有SPLP的PEG-二硬脂酰甘油（C1）绕过所谓的“首过”器官，包括肺，并在远端肿瘤组织中引发比在任何其他组织中观察到的高100至1000倍的基因表达水平。在SPLP中掺入PEG-S-DAG证实了小尺寸、低表面电荷和延长的循环寿命是全身施用后质粒DNA的积累和肿瘤选择性表达的先决条件。(C)2005 Elsevier B. V.保留所有权利。
Stabilized plasmid lipid particles (SPLP) consist of a single copy of DNA surrounded by a lipid bilayer, The particles are small (similar to 100 nm), stable, monodisperse and have a low surface charge. A diffusible polyethylene glycol (PEG) coating attached to a lipid anchor is critical to the SPLP's functionality. The PEG-lipid exchanges out of the bilayer at a rate determined by the size of the lipid anchor. Here we show that SPLP can be prepared using a series of PEG-diacylglycerol lipids (PEG-S-DAGs). SPLP were prepared incorporating PEG-dimyristoylglycerol (C-14), PEG-dipalmitoylglycerol (C-16) or PEG-distearoylglycerol (C-18) and the rate of PEG-lipid diffusion from the bi-layer determined using a FRET assay. SPLP pharmacokinetics confirm a correlation between the stability of the PEG-lipid component and circulation lifetime. PEG-S-DAGs with longer lipid anchors yield more stable SPLP particles with longer circulation half-lives yielding an increase in tumor delivery and gene expression. PEG-distearoylglycerol (C Is) containing SPLP bypass so-called 'first pass' organs, including the lung, and elicit levels of gene expression in distal tumor tissue 100- to 1000-fold greater than that observed in any other tissue. The incorporation of PEG-S-DAG in SPLP confirms that small size, low surface charge and extended circulation lifetimes are prerequisite to the accumulation and tumor selective expression of plasmid DNA following systemic administration. (C) 2005 Elsevier B.V. All rights reserved.