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在癌细胞中,PEG-ASO结合物可有效地向传递和抑制癌细胞迁移

Chunhui Zhao¹, Xiangjun Li¹, Zixin He¹

¹Hunan Huateng Pharmaceutical Co, Ltd., Changsha 410000, China; Changsha Institute of Innovative Pharmaceutical Industry, Changsha, 410000, China.

Bioorganic & medicinal chemistry letters

|March 26, 2025

概括

叶酸结合反感性寡核酸 (ASO) 显示瘤细胞吸收和基因沉默的增强. 这种叶酸-PEG-ASO平台为癌症治疗提供了一个有前途的策略.

科学领域:

生物技术是生物技术.
分子生物学分子生物学
癌症研究癌症研究

背景情况:

反感性寡核酸 (ASO) 通过向特定的RNA来抑制癌细胞生长.
聚乙烯甘醇 (PEG) 修改增强了ASO的稳定性,但在瘤细胞的特异性和吸收方面存在挑战.
针对特定的癌细胞机制对于有效的ASO疗法至关重要.

研究的目的:

为增强瘤细胞向开发和评估叶酸 (FA) 和maleimide联合修改的PEG结合抗miRNA-21ASO (FA-PEG-ASO).
评估FA-PEG-ASO在癌细胞中的细胞吸收,目标裂解效率和抗迁移作用.

主要方法:

合成FA和maleimide联合修饰的PEG.
修改PEG与通过提-马莱胺迈克尔添加的提修改抗miRNA-21 ASO的结合.
通过去除三-2-碳氧乙基) 氨酸化物 (TCEP) 来优化结合制剂的制备.
使用细胞成像来比较FA-PEG-ASO与对照HO-PEG-ASO的细胞吸收研究.
对点RNA裂变和瘤细胞迁移抑制的评估.

主要成果:

成功合成了FA-PEG-ASO,而TCEP的去除对于高产量至关重要.
细胞成像显示,与对照HO-PEG-ASO相比,FA-PEG-ASO的内部化程度大约是5倍.
FA-PEG-ASO表现出增强的抗miRNA-21点裂变.
FA-PEG-ASO显著降低了瘤细胞迁移的能力.

结论:

与未经修改的PEG-ASO相比,FA-PEG-ASO显示出优越的细胞吸收和增强的治疗效果.
FA-PEG-ASO结合体代表了癌症治疗的有前途的向治疗平台.
需要进一步研究FA-PEG-ASO在临床前癌症模型中的疗效.

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