Needham D, McIntosh T J, Lasic D D
Mechanical Engineering and Materials Science, Duke University, Durham, NC 27706.
Biochim Biophys Acta. 1992 Jul 8;1108(1):40-8. doi: 10.1016/0005-2736(92)90112-y.
Liposome membranes containing lipids with covalently attached poly(ethylene glycol) (PEG-lipid) are currently being developed as drug delivery systems. These, so called, 'Stealth' liposomes have a relatively long half life (approximately 1 day) in blood circulation and show an altered biodistribution in vivo. The extended lifetime appears to result from a steric stabilization of the liposome by the grafted polymer. In order to characterize the surface structures that promote steric stability in such polymer-grafted lipid bilayer systems, we have used X-ray diffraction to measure the structural organization and interbilayer repulsion for lipid/cholesterol (2:1) bilayers incorporating 4 mol% of a PEG-lipid in which the molecular weight of the PEG moiety was 1900 g/mol. At this concentration, applied pressure versus interbilayer distance relations showed that the grafted polymer moiety extended approximately 50 A from the lipid surface and gave rise to a strong, slowly decaying repulsive pressure between membranes that opposed their close approach. Also, the pressure vs. distance relations were only modestly altered by changing the ionic strength of the medium (1 mM NaCl and 100 mM NaCl). Therefore, even though the PEG-lipid headgroup bears a negative charge, the long range pressure cannot be due primarily to an electrostatic double layer pressure. Measurements of lipid bilayer elasticity using micropipet manipulation showed that PEG-lipid did not change the cohesive properties of lipid/cholesterol liposomes which was consistent with the X-ray structural data showing that the PEG-lipid did not change the normal structure of the bilayer interior. From these data we conclude that the repulsive barrier properties of lipid-grafted PEG polymer chains originate mainly from a steric pressure and that this simple polymer steric stabilization is the basis for the extended in vivo circulation times observed for polymer-grafted liposomes.
目前正在研发含有共价连接聚乙二醇（PEG-脂质）的脂质体膜作为药物递送系统。这些所谓的“隐形”脂质体在血液循环中的半衰期相对较长（约1天），并且在体内显示出改变的生物分布。延长的寿命似乎源于接枝聚合物对脂质体的空间稳定作用。为了表征在这种聚合物接枝脂质双层系统中促进空间稳定性的表面结构，我们使用X射线衍射来测量包含4摩尔％PEG-脂质（其中PEG部分的分子量为1900 g/mol）的脂质/胆固醇（2:1）双层的结构组织和双层间排斥力。在此浓度下，施加压力与双层间距离的关系表明，接枝的聚合物部分从脂质表面延伸约50埃，并在膜之间产生强烈的、缓慢衰减的排斥压力，阻止它们紧密靠近。此外，通过改变介质的离子强度（1 mM NaCl和100 mM NaCl），压力与距离的关系仅略有改变。因此，即使PEG-脂质头部带有负电荷，长程压力也不能主要归因于静电双层压力。使用微量移液器操作测量脂质双层弹性表明，PEG-脂质不会改变脂质/胆固醇脂质体的内聚性质，这与X射线结构数据一致，表明PEG-脂质不会改变双层内部的正常结构。从这些数据我们得出结论，脂质接枝PEG聚合物链的排斥屏障特性主要源于空间压力，并且这种简单的聚合物空间稳定作用是聚合物接枝脂质体在体内循环时间延长的基础。
