<br>多价乳糖酸和 N-乙酰半乳糖胺缀合肽核酸可有效体内靶向肝细胞,Advanced Healthcare Materials

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多价乳糖酸和 N-乙酰半乳糖胺缀合肽核酸可有效体内靶向肝细胞
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-01-13 , DOI: 10.1002/adhm.202202859
Vikas Kumar ₁ , Aniket Wahane ₁ , Anisha Gupta ₂ , José E Manautou ₁ , Raman Bahal ₁

Affiliation

肽核酸 (PNA) 在各种研究中用于靶向基因组 DNA 和 RNA 以调节基因表达。对于基于 PNA 的应用来说，非特异性靶向和快速消除始终是一个挑战。本文报道了用于肝脏靶向递送的双乳糖酸 (diLBA) 和三 N-乙酰半乳糖胺 (tGalNAc) 缀合 PNA 的合成、表征以及体外和体内研究。为了证明概念，合成了 diLBA 和 tGalNAc 缀合的 PNA（抗 miR-122 PNA）以靶向在肝组织中过度表达的 microRNA-122 (miR-122)。测试了与 diLBA 和 tGalNAc 缀合的不同长度的抗 miR-122 PNA。进行细胞培养和体内分析以确定生物分布、功效和毒性特征。这项工作表明，除了 tGalNAc 缀合物外，diLBA 缀合物在体内递送后在肝细胞中也显示出显着的保留。全长 PNA 缀合物显示 miR-122 水平显着下调，并随后解除其下游靶标的抑制，且没有毒性证据。这些结果为 PNA 的配体缀合递送系统提供了一个强大的框架，可以探索更广泛的生物医学应用。

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Multivalent Lactobionic Acid and N-Acetylgalactosamine-Conjugated Peptide Nucleic Acids for Efficient In Vivo Targeting of Hepatocytes

Peptide nucleic acids (PNAs) are used/applied in various studies to target genomic DNA and RNA to modulate gene expression. Non-specific targeting and rapid elimination always remain a challenge for PNA-based applications. Here, the synthesis, characterization, in vitro and in vivo study of di lactobionic acid (diLBA) and tris N-acetyl galactosamine (tGalNAc) conjugated PNAs for liver-targeted delivery are reported. For proof of concept, diLBA, and tGalNAc conjugated PNAs (anti-miR-122 PNAs) were synthesized to target microRNA-122 (miR-122) which is over-expressed in the hepatic tissue. Different lengths of anti-miR-122 PNAs conjugated with diLBA and tGalNAc are tested. Cell culture and in vivo analyses to determine biodistribution, efficacy, and toxicity profile are performed. This work indicates that diLBA conjugates show significant retention in hepatocytes in addition to tGalNAc conjugates after in vivo delivery. Full-length PNA conjugates show significant downregulation of miR-122 levels and subsequent de-repression of its downstream targets with no evidence of toxicity. The results provide a robust framework for ligand-conjugated delivery systems for PNAs that can be explored for broader biomedical applications.

更新日期：2023-01-13

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