EFFECT OF LIPOSOME SIZE ON THE CIRCULATION TIME AND INTRAORGAN DISTRIBUTION OF AMPHIPATHIC POLY(ETHYLENE GLYCOL)-CONTAINING LIPOSOMES
EFFECT OF LIPOSOME SIZE ON THE CIRCULATION TIME AND INTRAORGAN DISTRIBUTION OF AMPHIPATHIC POLY(ETHYLENE GLYCOL)-CONTAINING LIPOSOMES
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DOI：
10.1016/0005-2736(94)90038-8
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发表时间：
1994-02-23
影响因子：
3.4
通讯作者：
HUANG, L
中科院分区：
文献类型：
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作者：
LITZINGER, DC;BUITING, AMJ;HUANG, L
制备含有二乙酰基-N-（单甲氧基聚（乙二醇）琥珀酰）-磷脂酰乙醇胺（PEG-PE）和三种特征尺寸（d > 300 nm、d 类似于 150-200 nm 和 d < 70 nm）的脂质体，注射到小鼠体内，并根据放射性脂质相标记检查其生物分布。大脂质体和小脂质体分别在脾脏和肝脏中积累至升高的水平。发现中等大小的脂质体循环时间最长。此外，当注射到携带小鼠MC-38结肠癌肿瘤的小鼠中时，与不含PEG-PE的脂质体相比，观察到长循环脂质体每克肿瘤的％注射剂量增加了大约2倍。通过荧光显微镜检查注射的脂质体在肿瘤内的分布，其中脂质体用1,1'-双十八烷基-3,3,3',3'-四甲基吲哚羰花青高氯酸盐(DiI)标记。在肿瘤的血管周围发现了脂质体，并有一定程度的外渗到肿瘤块中。先前对小脂质体循环时间缩短的解释是，它们能够穿过有孔的肝内皮，从而到达实质细胞。因此，使用 DiI 标记的脂质体来检查注射脂质体的肝内分布。无论脂质体大小如何，肝脏中积累的脂质体都定位于库普弗细胞。当使用这种荧光技术时，在由实质细胞组成的区域中检测不到小脂质体。小脂质体长循环行为降低的原因可能与PEG-PE的活性更直接相关。因此，通过血清蛋白结合测定和通过链霉抗生物素蛋白与生物素化脂质体的结合来检查脂质体的空间屏障活性。空间屏障取决于脂质体大小，小脂质体显示蛋白质结合增加。小脂质体空间屏障的降低可能导致对调理作用的敏感性增加，从而解释了它们从循环中更快的清除。脾脏中积累的大脂质体位于红髓和边缘区。大脂质体的吸收可以通过过滤机制发生。这些结果确立了脂质体尺寸在确定脂质体循环时间和生物分布中的重要性，并且与用于药物递送的脂质体的优化设计相关。
Liposomes containing dioieoyl-N-(monomethoxypoly(ethylene glycol)succinyl)-phosphatidylethanolamin (PEG-PE), and of three characteristic sizes (d > 300 nm, d similar to 150-200 nm, and d < 70 nm), were prepared, injected into mice, and their biodistributions examined following a radioactive lipid phase marker. The large and small liposomes accumulated to elevated levels in spleen and liver, respectively. The intermediate sized liposomes were found to be the longest circulating. Furthermore, when injected into mice bearing murine MC-38 colon carcinoma tumor, an approximate 2-fold increase in the % injected dose per g tumor was observed for the long-circulating liposomes compared to liposomes without PEG-PE. The distribution of the injected liposomes within the tumor was examined by fluorescence microscopy, where the liposomes were labeled with 1,1'-dioctadecyl-3,3,3 ',3 '-tetramethylindocarbocyanine perchlorate (DiI). The liposomes were found surrounding blood vessels in the tumor, with some degree of extravasation into the tumor mass. A previous explanation for the reduced circulation time of small liposomes has been that they have an ability to pass through the fenestrated liver endothelium and thereby reach the parenchymal cells. DiI-labeled liposomes were therefore used to examine the intrahepatic distribution of the injected liposomes. Liposomes accumulated in liver were localized to Kupffer cells, regardless of liposome size. The small liposomes were not detectable in areas comprised of parenchymal cells when using this fluorescence technique. The reason for reduced long-circulating behavior for the small liposomes may be more directly related to the activity of PEG-PE. Therefore the steric barrier activity of the liposomes was examined by a serum protein binding assay and by streptavidin binding to biotinylated liposomes. The steric barrier was liposome size dependent, with the small liposomes revealing increased protein binding. This decreased steric barrier of the small liposomes may result in increased susceptibility to opsonization and thus explain their more rapid clearance from the circulation. The large liposomes accumulated in spleen were localized in the red pulp and marginal zone. Uptake of the large liposomes may occur by means of a filtration mechanism. These results establish the significance of liposome size in determining liposome circulation time and biodistribution, and are relevant for the optimal design of liposomes for drug delivery.