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Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics
Molecular Therapy ( IF 12.1 ) Pub Date : 2022-08-06 , DOI: 10.1016/j.ymthe.2022.07.015
John G Yuen 1 , Andrew Fesler 2 , Ga-Ram Hwang 1 , Lan-Bo Chen 2 , Jingfang Ju 3
Affiliation  

MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.



中文翻译:

开发 5-FU 修饰的肿瘤抑制 microRNA 作为新型基于 microRNA 的癌症治疗的平台

MicroRNA (miRNA) 是基因表达的多效性转录后调节剂。其固有的多效性使 miRNA 成为开发癌症疗法的有力候选者,但尽管它们具有潜力,但将基于核酸的疗法传递到癌细胞中仍然存在挑战。我们开发了一种新的修饰miRNA的方法,通过将抑癌miRNA引导链中的尿嘧啶碱基替换为5-氟尿嘧啶(5-FU),从而将5-FU的治疗作用与miRNA的抑癌作用相结合,创造出一种新型的miRNA修饰方法。有效的多靶点治疗分子,而不改变其天然 RNAi 功能。为了证明这种方法对其他肿瘤抑制 miRNA 的普遍适用性,我们在多种癌症类型中筛选了一组 12 种新型 miRNA 模拟物,包括白血病、乳腺癌、胃癌、肺癌和胰腺癌。我们的结果表明,5-FU 修饰的 miRNA 模拟物在抑制癌细胞增殖方面具有增强的效力(低纳摩尔范围),并且这些模拟物可以在体外体内无需递送载体的情况下递送到癌细胞中,从而代表了癌症治疗领域的重大进步。开发癌症治疗性 miRNA。这项工作展示了氟嘧啶修饰的潜力,其可广泛应用,并可作为未来 miRNA 和核酸治疗的平台技术。

更新日期:2022-08-06
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