N-乙酰半乳糖胺偶联寡核苷酸的肝脏靶向递送,ACS Omega

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N-乙酰半乳糖胺偶联寡核苷酸的肝脏靶向递送
ACS Omega ( IF 3.7 ) Pub Date : 2021-06-14 , DOI: 10.1021/acsomega.1c01755
Hao Cui ₁ , Xinying Zhu ₁ , Shuyue Li ₁ , Peipei Wang _{2,

3} , Jianping Fang ₄

Affiliation

通过反义和 RNA 干扰机制选择性抑制靶基因的寡核苷酸 (ONs) 的潜在治疗应用引起了极大的关注。ONs的临床应用克服了多重障碍，成为开发新疗法最活跃的领域之一。为了实现高效和特异性的细胞内化，在过去十年中，将各种功能基团与 ON 结合一直是深入研究的主题。其中，一种有前景的肝脏靶向N-乙酰半乳糖胺 (GalNAc) 配体已在多项临床前和临床试验中得到评估，以改善 ON 的细胞摄取和组织特异性递送。基于 GalNAc 的递送依赖于以下事实：肝细胞大量且特异性地表达无唾液酸糖蛋白受体，该受体通过受体介导的内吞作用结合和摄取循环糖蛋白。近年来，GalNAc 偶联物领域取得了令人鼓舞的进展。本综述旨在概述 GalNAc 介导的肝脏靶向递送小干扰 RNA 和反义寡核苷酸，并描述了 GalNAc 偶联药物开发方面的巨大努力和最新进展。

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Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation

The potential therapeutic application of oligonucleotides (ONs) that selectively suppress target genes through antisense and RNA interference mechanisms has attracted great attention. The clinical applications of ONs have overcome multiple obstacles and become one of the most active areas for the development of novel therapeutics. To achieve efficient and specific cellular internalization, conjugation of a variety of functional groups to ONs has been the subject of intensive investigations over the past decade. Among them, a promising liver-targeted N-acetylgalactosamine (GalNAc) ligand has been evaluated in multiple preclinical and clinical trials for improving the cellular uptake and tissue specific delivery of ONs. GalNAc-based delivery relies on the fact that liver hepatocytes abundantly and specifically express the asialoglycoprotein receptor that binds and uptakes circulating glycoproteins via receptor-mediated endocytosis. In recent years, encouraging progress has been made in the field of GalNAc conjugates. This review aims to provide an overview of GalNAc-mediated liver-targeted delivery of small interfering RNA and antisense oligonucleotides, and the immense effort as well as recent advances in the development of GalNAc-conjugated agents are described.

更新日期：2021-06-29

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