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Conjugating aptamer and mitomycin C with reductant-responsive linker leading to synergistically enhanced anti-cancer effect
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-01-07 , DOI: 10.1021/jacs.9b12409
Qiuxia Yang 1 , Zhengyu Deng 1 , Dan Wang 1 , Jiaxuan He 1 , Dailiang Zhang 1 , Yan Tan 1 , Tianhuan Peng 1 , Xue-Qiang Wang 1 , Weihong Tan 1, 2, 3
Affiliation  

Mitomycin C (MMC) has been using for the treatment of a variety of digestive tract cancers. However, its nonspecific DNA-alkylating ability usually causes severe side effects, thus largely limiting its clinical applications. The utilization of an efficient active targeted drug delivery technique would address this issue. Accordingly, we report the design and development of aptamer-mitomycin C conjugates that uses different crosslinking chemistry. The targeted delivery ability and cytotoxicity of these conjugates were carefully studied. It is worth noting that a linker-dependent cytotoxicity effect was observed for these conjugates. The use of a reductant-sensitive disulfide bond crosslinking strategy resulted in significantly enhanced cytotoxicity of MMC against the target cancer cell lines. Importantly, this cytotoxicity enhancement was suited to different types of aptamers, demonstrating the success of our design. Mechanistic studies of the enhanced cytotoxicity effect indicated that the target recognition, specific binding, and receptor-mediated internalization of aptamer were also critical for the observed effect.

中文翻译:

将适体和丝裂霉素 C 与还原剂响应接头结合,导致协同增强的抗癌作用

丝裂霉素 C (MMC) 已用于治疗多种消化道癌症。然而,其非特异性 DNA 烷基化能力通常会引起严重的副作用,从而在很大程度上限制了其临床应用。使用有效的主动靶向药物递送技术将解决这个问题。因此,我们报告了使用不同交联化学的适体-丝裂霉素 C 偶联物的设计和开发。仔细研究了这些缀合物的靶向递送能力和细胞毒性。值得注意的是,这些偶联物观察到了依赖于接头的细胞毒性效应。使用还原剂敏感的二硫键交联策略显着增强了 MMC 对靶癌细胞系的细胞毒性。重要的,这种细胞毒性增强适用于不同类型的适体,证明了我们设计的成功。增强细胞毒性效应的机制研究表明,适体的靶标识别、特异性结合和受体介导的内化对于观察到的效应也至关重要。
更新日期:2020-01-07
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