Shimada K, Kamps J A, Regts J, Ikeda K, Shiozawa T, Hirota S, Scherphof G L
University of Groningen, Groningen Institute for Drug Studies, Faculty of Medical Sciences, Department of Physiological Chemistry, The Netherlands.
Biochim Biophys Acta. 1997 Jun 12;1326(2):329-41. doi: 10.1016/s0005-2736(97)00036-9.
We describe the synthesis of biodegradable poly(ethyleneglycol)-coupled galactolipids in which the galactose moiety is separated from a diacylglyceride lipid anchor by poly(ethylene glycol) chains of 10, 20 or 40 oxyethylene residues (PEG10/20/40). These Gal-PEG lipids (Gal-PEG-Lip) were incorporated in the bilayer of liposomes. The surface exposure of the galactose was investigated by aggregation experiments with ricinus communis agglutinin 120. Only the liposomes containing the PEG10 galactolipid aggregated with the lectin. Therefore liposomes were prepared containing Gal-PEG10-Lip and a trace amount of [3H]cholesteryl oleyl ether with an average diameter of approximately 100 nm and injected intravenously into rats. The Gal-PEG10-Lip liposomes were cleared from plasma with a T1/2 of 0.3 h. Identically sized and composed control liposomes without the Gal-PEG10-Lip had a T1/2 of approximately 12 h. The rapid plasma elimination of the Gal-PEG10-Lip liposomes could be attributed entirely to increased uptake by the liver amounting to more than 90% of injected dose. Uptake by the spleen was decreased to less than 1% of injected dose. A single injection of N-acetylgalactosamine 1 min prior to Gal-PEG-Lip liposome administration reduced the initial rate of plasma clearance to control levels. The increased liver uptake was almost entirely attributable to increased uptake by the Kupffer cells. Incorporation of PEG-DSPE in the Gal-PEG10-Lip liposomes only partially reversed the effect of the galactolipid with respect to liver and spleen uptake as well as intrahepatic distribution. These experiments demonstrate that liposome surface-exposed galactose residues, even if attached at the distal end of a poly(ethyleneglycol) chain anchored in the liposomal bilayer are effectively recognized by the galactose particle receptor on the Kupffer cells but fail to achieve significant targeting to the asialoglycoprotein receptor on the hepatocytes.
我们描述了可生物降解的聚乙二醇偶联半乳糖脂的合成，其中半乳糖部分通过具有10、20或40个氧化乙烯残基的聚乙二醇链（PEG10/20/40）与二酰基甘油脂质锚定基团分离。这些半乳糖-聚乙二醇脂质（Gal-PEG-Lip）被掺入脂质体双层中。通过与蓖麻凝集素120进行聚集实验研究了半乳糖的表面暴露情况。只有含有PEG10半乳糖脂的脂质体与凝集素聚集。因此，制备了含有Gal-PEG10-Lip和痕量[3H]胆固醇油醚的脂质体，其平均直径约为100nm，并静脉注射到大鼠体内。Gal-PEG10-Lip脂质体从血浆中清除的半衰期为0.3小时。不含Gal-PEG10-Lip的大小和组成相同的对照脂质体的半衰期约为12小时。Gal-PEG10-Lip脂质体在血浆中的快速清除完全归因于肝脏摄取增加，占注射剂量的90%以上。脾脏摄取降至注射剂量的1%以下。在给予Gal-PEG-Lip脂质体前1分钟单次注射N-乙酰半乳糖胺可将血浆清除的初始速率降低至对照水平。肝脏摄取增加几乎完全归因于库普弗细胞摄取增加。在Gal-PEG10-Lip脂质体中掺入PEG-DSPE仅部分逆转了半乳糖脂对肝脏和脾脏摄取以及肝内分布的影响。这些实验表明，脂质体表面暴露的半乳糖残基，即使连接在锚定在脂质体双层中的聚乙二醇链的远端，也能被库普弗细胞上的半乳糖颗粒受体有效识别，但未能实现对肝细胞上脱唾液酸糖蛋白受体的显著靶向。
