In this study, we describe a novel synthesis of galactosylated lipids by lipase catalysis. Lactitol (Lac), galactose (Gal), or N-acetyl galactosamine (GalNAc) was coupled with cholesterol (CHS) as target head groups by enzyme-catalyzed regioselective esterification to produce three kinds of lipids: CHS-1-Gal, CHS-6-Gal, or CHS-6-GalNAc1. The biological effects of galactosylated lipids carrying different constitutional isomers of the pendent sugar species were investigated. LP-1-Gal (liposomes containing 5.0 molar% of CHS-1-Gal) showed strong binding to tetrameric lectins of Ricinus communis agglutinin (RCA120) in vitro, while LP-6-Gal (liposomes containing 5.0 molar% of CHS-6-Gal) and LP-6-GalNAc (liposomes containing 5.0 molar% of CHS-6-GalNAc) did not. After intravenous injection, LP-6-GalNAc, LP-1-Gal and LP-6-Gal rapidly disappeared from the blood and accumulated rapidly in liver (up to 74.88 ± 4.11%, 58.67 ± 5.75%, and 47.66 ± 4.56% of injected dose/g organ within 4 h, respectively). This is significantly higher than the uptake of unmodified liposomes (Unmod-LP) (18.67 ± 6.07%). Pre-injection of asialofetuin significantly inhibits liver uptake of Gal-liposomes (P < 0.01), with the degree of inhibition appearing in the following order: LP-6-GalNAc (73.29%) > LP-1-Gal (67.06%) > LP-6-Gal (53.61%). More importantly, LP-6-GalNAc was preferentially taken up by hepatocytes and the uptake ratio by parenchymal cells (PC) and nonparenchymal cells (NPC) (PC/NPC ratio) was 11.03 higher than LP-1-Gal (7.32), LP-6-Gal (5.83) and Unmod-LP (2.39). We suggest that liposomes containing the novel galactosylated lipid CHS-6-GalNAc have potential as drug delivery carriers for hepatocyte-selective targeting.

中文翻译：

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半乳糖基化脂质体中gal/GalNAc区域异构对去唾液酸糖蛋白受体介导的体内肝细胞选择性靶向的影响

在这项研究中，我们描述了一种通过脂肪酶催化合成半乳糖基化脂质的新方法。乳糖醇 (Lac)、半乳糖 (Gal) 或 N-乙酰半乳糖胺 (GalNAc) 与作为目标头基的胆固醇 (CHS) 通过酶催化区域选择性酯化反应产生三种脂质：CHS-1-Gal、CHS- 6-Gal 或 CHS-6-GalNAc1。研究了携带悬垂糖类的不同结构异构体的半乳糖基化脂质的生物学效应。LP-1-Gal（含有 5.0 摩尔% CHS-1-Gal 的脂质体）在体外表现出与蓖麻凝集素（RCA120）四聚体凝集素的强结合，而 LP-6-Gal（含有 5.0 摩尔% CHS-6 的脂质体） -Gal) 和 LP-6-GalNAc（含有 5.0 摩尔% CHS-6-GalNAc 的脂质体）没有。静脉注射LP-6-GalNAc后，LP-1-Gal 和 LP-6-Gal 从血液中迅速消失并在肝脏中迅速积累（4 小时内分别高达注射剂量的 74.88 ± 4.11%、58.67 ± 5.75% 和 47.66 ± 4.56%/g 器官） ）。这明显高于未修饰脂质体 (Unmod-LP) (18.67 ± 6.07%) 的吸收。预注射去唾液酸胎球蛋白显着抑制肝脏对Gal-脂质体的摄取（P < 0.01），抑制程度依次为：LP-6-GalNAc (73.29%) > LP-1-Gal (67.06%) > LP-6-Gal (53.61%)。更重要的是，LP-6-GalNAc 优先被肝细胞摄取，实质细胞（PC）和非实质细胞（NPC）的摄取比（PC/NPC 比）比 LP-1-Gal（7.32）高 11.03，LP -6-Gal (5.83) 和 Unmod-LP (2.39)。