ACTIVITY OF AMPHIPATHIC POLY(ETHYLENE GLYCOL)-5000 TO PROLONG THE CIRCULATION TIME OF LIPOSOMES DEPENDS ON THE LIPOSOME SIZE AND IS UNFAVORABLE FOR IMMUNOLIPOSOME BINDING TO TARGET
ACTIVITY OF AMPHIPATHIC POLY(ETHYLENE GLYCOL)-5000 TO PROLONG THE CIRCULATION TIME OF LIPOSOMES DEPENDS ON THE LIPOSOME SIZE AND IS UNFAVORABLE FOR IMMUNOLIPOSOME BINDING TO TARGET
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DOI：
10.1016/0005-2736(91)90385-l
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发表时间：
1991-02-25
期刊：
影响因子：
--
通讯作者：
HUANG, L
中科院分区：
文献类型：
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作者：
KLIBANOV, AL;MARUYAMA, K;HUANG, L
二油酰基-N-(单甲氧基聚乙二醇丁二醇)-磷脂酰乙醇胺(PEGPE)(摩尔数)聚乙二醇的重量=5000)，两亲性聚合物可以被结合到脂质体的膜中，并显著延长脂质体的血液循环时间。在脂质体中加入3.7mol%的聚乙二醇PE，可最大限度地延长脂质体的循环时间。然而，只有相对较小的脂质体(d小于或等于200 nm)才能看到聚乙二醇-PE的这种活性；含有聚乙二醇-PE的较大脂质体显示出异常高的水平(约。注射剂量的35%)在脾内蓄积。我们已经通过在脂质体表面加入肺特异性单抗来测试含有聚乙二醇PE的小脂质体是否适合作为免疫靶向。而另一种两亲性分子神经节苷脂GM1能显著提高免疫脂质体的肺结合能力，而聚乙二醇乙二醇酯(PEGPE)的掺入则导致低水平的靶结合。为了测试靶标结合的减少是否由于表面聚乙二醇酯聚合物的空间位阻效应，我们将少量的N-生物氨丙基磷脂酰乙醇胺加入到含有聚乙二醇乙醇酯的脂质体中，并检测了添加链霉亲和素引起的脂质体凝集。在这些脂质体中加入0.72mol%的PEGPE后，凝集完全消失。相反，在脂质体中加入GM1只会降低脂质体的凝集速度，但不会降低脂质体的凝集程度。这些结果有力地支持了这样一种假设，即聚乙二醇PE通过提供一个强大的立体屏障来延长脂质体的循环时间，从而防止与另一个脂质体或细胞的近距离接触。由于GM1只提供了一种微弱的空间屏障效应，它延长脂质体循环时间的活性肯定涉及另一种未知的机制。
Dioleoyl-N-(monomethoxy polyethyleneglycol succinyl)-phosphatidylethanolamine (PEG-PE) (mol. wt. of PEG = 5000), an amphipathic polymer, can be incorporated into the liposome membrane and significantly prolong the blood circulation time of the liposome. As little as 3.7 mol% of PEG-PE in liposome resulted in maximal enhancement of liposome circulation time. However, this activity of PEG-PE was only seen with relatively small liposomes (d less-than-or-equal-to 200 nm); larger liposomes containing PEG-PE showed an unusually high level (approx. 35% injected dose) of accumulation in the spleen. We have tested whether the small, PEG-PE containing liposomes are suitable for immuno targeting by incorporating a lung-specific monoclonal antibody on the liposome surface. While another amphiphile, ganglioside GM1, which is well known for its activity to prolong the liposome circulation time, significantly enhanced the lung binding of the immunoliposomes, PEG-PE incorporation of immunoliposomes resulted in a low level of target binding. To test if the reduced target binding is due to a steric barrier effect of the surface PEG polymer, we have incorporated a small amount of N-biotinaminocaproylphosphatidylethanolamine into the PEG-PE containing liposomes and examined the liposome agglutination induced by the addition of streptavidin. As little as 0.72 mol% PEG-PE in these liposomes completely abolished agglutination. In contrast, incorporation of GM1 in liposomes only reduced the rate, but not the extent, of liposome agglutination. These results strongly support the hypothesis that PEG-PE prolongs liposome circulation time by providing a strong steric barrier which prevents close contact with another liposome or cell. Since GM1 provides only a weak steric barrier effect, its activity to prolong the liposome circulation time must involve another yet unknown mechanism.