Programmed Instability of Ligand Conjugation Manifold for Efficient Hepatocyte Delivery of Therapeutic Oligonucleotides

寡核苷酸 体内 内化 配体(生物化学) 化学 核酸 药物输送 生物物理学 受体 细胞生物学 生物化学 生物 DNA 生物技术 有机化学
作者
Chisato Terada,Fumito Wada,Mei Uchida,Yukari Yasutomi,Kaho Oh,Seiya Kawamoto,Yukina Kayaba,Asako Yamayoshi,Mariko Harada‐Shiba,Satoshi Obika,Tsuyoshi Yamamoto
出处
期刊:Nucleic Acid Therapeutics [Mary Ann Liebert]
卷期号:31 (6): 404-416 被引量:6
标识
DOI:10.1089/nat.2021.0036
摘要

Ligand-targeted drug delivery (LTDD) has gained more attention in the field of nucleic acid therapeutics. To further elicit the potential of therapeutic oligonucleotides by means of LTDD, we newly developed (R)- and (S)-3-amino-1,2-propanediol (APD) manifold for ligand conjugation. N-acetylgalactosamine (GalNAc)/asialoglycoprotein receptor (ASGPr) system has been shown to be a powerful and robust paradigm of LTDD. Our novel APD-based GalNAc (GalNAcAPD) was shown to have intrinsic chemical instability that could play a role in better manipulation of active drug release. The APD manifold also enables facile production of conjugates through an on-support ligand cluster synthesis. We showed in a series of in vivo studies that while the knockdown activity of antisense oligonucleotides (ASOs) bearing 5'-GalNAcAPD was comparable to the conventional hydroxy-L-prolinol-linked GalNAc (GalNAcHP), 3'-GalNAcAPD elicited ASO activity by more than twice as much as the conventional 3'-GalNAcHP. This was ascribed partly to the GalNAcAPD's ideal susceptibility to nucleolytic digestion, which is expected to facilitate cytosolic internalization of ASO drugs. Moreover, an in vivo/ex vivo imaging study visualized the enhancement effect of monoantennary GalNAcAPD on liver localization of ASOs. This versatile manifold with chemical and biological instability would benefit therapeutic oligonucleotides that target both the liver and extrahepatic tissues.
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