Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: Relating plasma circulation lifetimes to protein binding
Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: Relating plasma circulation lifetimes to protein binding
复制标题
DOI：
10.1016/j.bbamem.2006.12.013
复制
发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
Bally, Marcel B.
中科院分区：
文献类型：
--
作者：
Dos Santos, Nancy;Allen, Christine;Bally, Marcel B.
将聚（乙二醇）（PEG）缀合的脂质掺入基于脂质的载体中基本上延长了脂质体的循环寿命。然而，PEG-脂质实现这一点的机制尚未完全阐明。据信PEG-脂质介导空间稳定，最终减少表面-表面相互作用，包括脂质体的聚集和/或血浆蛋白的吸附。本文所述研究的目的是比较脂质体中PEG-脂质掺入对小鼠中蛋白质结合、脂质体-脂质体聚集和药代动力学的影响。选择不含胆固醇的脂质体是因为它们作为脂质体递送系统的重要性日益增加以及它们对蛋白质结合和聚集的显著敏感性。具体而言，分析了含有各种摩尔比例的各种分子量PEG-脂质的脂质体的体内清除率、聚集状态（尺寸排阻色谱法、准弹性光散射、冷冻透射和冷冻断裂电子显微术）以及体外和体内蛋白结合。结果表明，用平均分子量为2000的PEG（DSPE-PEG（2000））修饰的低至0.5mol%的1，2-二硬脂酰-sn-甘油基-3-磷脂酰乙醇胺（DSPE）显著增加了由1，2-二硬脂酰-sn-甘油基-3-磷脂酰胆碱（DSPC）制备的脂质体的血浆循环寿命。使用2 mol% DSPE-PEG（2000）可获得最佳血浆循环寿命。在DSPE-PEG（2000）的该比例下，完全排除了基于DSPC的脂质体的聚集。然而，膜中DSPE-PEG（2000）的水平不影响总蛋白吸附和蛋白质谱。这些研究表明，PEG-脂质主要通过抑制表面相互作用，特别是脂质体-脂质体聚集，降低无胆固醇脂质体制剂的体内清除率。(c)2007 Elsevier B. V.保留所有权利。
The incorporation of poly(ethylene glycol) (PEG)-conjugated lipids in lipid-based carriers substantially prolongs the circulation lifetime of liposomes. However, the mechanism(s) by which PEG-lipids achieve this have not been fully elucidated. It is believed that PEG-lipids mediate steric stabilization, ultimately reducing surface-surface interactions including the aggregation of liposomes and/or adsorption of plasma proteins. The purpose of the studies described here was to compare the effects of PEG-lipid incorporation in liposomes on protein binding, liposome-liposome aggregation and pharmacokinetics in mice. Cholesterol-free liposomes were chosen because of their increasing importance as liposomal delivery systems and their marked sensitivity to protein binding and aggregation. Specifically, liposomes containing various molecular weight PEG-lipids at a variety of molar proportions were analyzed for in vivo clearance, aggregation state (size exclusion chromatography, quasi-elastic light scattering, cryo-transmission and freeze fracture electron microscopy) as well as in vitro and in vivo protein binding. The results indicated that as little as 0.5 mol% of 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) modified with PEG having a mean molecular weight of 2000 (DSPE-PEG(2000)) substantially increased plasma circulation longevity of liposomes prepared of 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC). Optimal plasma circulation lifetimes could be achieved with 2 mol% DSPE-PEG(2000). At this proportion of DSPE-PEG(2000), the aggregation of DSPC-based liposomes was completely precluded. However, the total protein adsorption and the protein profile was not influenced by the level of DSPE-PEG(2000) in the membrane. These studies suggest that PEG-lipids reduce the in vivo clearance of cholesterol-free liposomal formulations primarily by inhibition of surface interactions, particularly liposome-liposome aggregation. (c) 2007 Elsevier B.V. All rights reserved.