Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications.
Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications.
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DOI：
10.2741/a806
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发表时间：
2002-03
期刊：
影响因子：
--
通讯作者：
Jian Wu;M. Nantz;M. Zern
中科院分区：
文献类型：
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作者：
Jian Wu;M. Nantz;M. Zern
哺乳动物肝细胞上的asialal糖蛋白受体（ASGP-R）为肝脏特异性载体（如脂质体、重组脂蛋白和聚合物）的发展提供了一种独特的手段，用于将药物或基因递送到肝脏，特别是肝细胞。细胞上丰富的受体特异性地识别带有末端半乳糖或n -乙酰半乳糖胺残基的配体，并内吞配体进行细胞内降解过程。使用其天然配体，即asialofetuin，或具有半乳糖基化或乳糖基化残基的合成配体，如半乳糖基化胆固醇、糖脂或半乳糖基化聚合物，对肝脏具有显著的靶向作用。有几个成功的靶向治疗急性肝损伤的例子，使用asialofetin标记的和维生素e相关的脂质体或在载糖聚合物颗粒中装载的caspase抑制剂，以及递送一种新的抗病毒药物，9-（2-膦基甲氧基乙基）腺嘌呤。脂质体介导的基因传递到肝脏比传递到其他器官（如肺）要困难得多。由于难以解决一般问题，例如脂质体-DNA复合物的循环稳定性以及质粒DNA的溶酶体或内体降解，因此它仍处于起步阶段。尽管存在这些现有的担忧，但一些新的方法提供了一些乐观的理由，例如；静脉注射asialfetuin或半乳糖化胆固醇标记的阳离子脂质体导致肝脏中高转基因表达。此外，将抗土拨鼠肝炎病毒的特异性反义寡核苷酸掺入唾液样体-聚l -赖氨酸中，可显著抑制病毒在肝脏中的复制。最后，半乳糖基化聚合物有望用于基因传递，但需要进一步的研究来验证其潜在的应用。
The asialoglycoprotein receptor (ASGP-R) on mammalian hepatocytes provides a unique means for the development of liver-specific carriers, such as liposomes, recombinant lipoproteins, and polymers for drug or gene delivery to the liver, especially to hepatocytes. The abundant receptors on the cells specifically recognize ligands with terminal galactose or N-acetylgalactosamine residues, and endocytose the ligands for an intracellular degradation process. The use of its natural ligand, i.e. asialofetuin, or synthetic ligands with galactosylated or lactosylated residues, such as galactosylated cholesterol, glycolipids, or galactosylated polymers has achieved significant targeting efficacy to the liver. There are several examples of successful targeted therapy for acute liver injury with asialofetuin-labeled and vitamin E-associated liposomes or with a caspase inhibitor loaded in sugar-carrying polymer particles, as well as for the delivery of a new antiviral agent, 9-(2-phosphonylmethoxyethyl)adenine. Liposome-mediated gene delivery to the liver is more difficult than to other organs, such as to lungs. It is still in its infancy due to difficulties in solving general issues, such as the circulatory stability of liposome-DNA complexes, and lysosomal or endosomal degradation of plasmid DNA. In spite of these existing concerns, several new approaches offer some reason for optimism, for example; intravenous injection of asialofetuin- or galactosylated cholesterol-labeled cationic liposomes has led to high transgene expression in the liver. In addition, specific antisense oligonucleotides against woodchuck hepatitis viruses incorporated into sialoorosomucoid-poly-L-lysine significantly inhibited viral replication in the liver. Finally, galactosylated polymers are promising for gene delivery, but require further studies to verify their potential applications.