PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-24 DOI:10.1016/j.bmcl.2025.130208

Chunhui Zhao , Xiangjun Li , Zixin He , Chun Ye , Feng Chen , Jia Cheng

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Abstract

Antisense oligonucleotides (ASO) specifically bind target RNAs resulted in gene silencing, thereby inhibiting cancer cell growth. Chemical modification based on polyethylene glycol (PEG) usually improve resistance to nuclease degradation. However, the specificity and cellular uptake of PEG-conjugated ASOs for tumor cells is still a challenge. In this work, the folate (FA) and maleimide co-modified PEG was prepared and bound with thiol-modified anti-miRNA-21 ASO to form the FA-PEG-ASO conjugates by thiol-maleimide Michael addition. During the FA-PEG-ASO preparation process, removing tris-(2-carboxyethyl) phosphine hydrochloride (TCEP) is the key for the high yields. Cell imaging results showed FA-PEG-ASO internalized by the cells taken up ∼5 times higher than the control HO-PEG-ASO prepared by maleimide modified PEG and anti-miRNA-21 ASO. In addition, FA-PEG-ASO exhibited higher target cleavage and a greater reduction in tumor cell migration ability. Together, FA-PEG-ASO is a promising therapeutic platform.

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PEG-ASO偶联物在肿瘤细胞中的有效靶向递送和迁移抑制

反义寡核苷酸（ASO）特异性结合靶rna导致基因沉默，从而抑制癌细胞生长。基于聚乙二醇（PEG）的化学改性通常可以提高对核酸酶降解的抵抗力。然而，peg共轭ASOs对肿瘤细胞的特异性和细胞摄取仍然是一个挑战。本文制备了叶酸（FA）和马来酰亚胺共修饰的PEG，并与巯基修饰的抗mirna -21 ASO结合，通过巯基马来酰亚胺Michael加成形成FA-PEG-ASO偶联物。在FA-PEG-ASO制备过程中，去除三-（2-羧基乙基）磷酸盐酸盐（TCEP）是提高收率的关键。细胞成像结果显示，与由马来酰亚胺修饰的PEG和抗mirna -21 ASO制备的对照HO-PEG-ASO相比，FA-PEG-ASO被吸收的细胞内化率高~ 5倍。此外，FA-PEG-ASO表现出更高的靶切割能力和更大的肿瘤细胞迁移能力的降低。总之，FA-PEG-ASO是一个很有前景的治疗平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.