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Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution.
Communications Biology ( IF 5.2 ) Pub Date : 2020-01-15 , DOI: 10.1038/s42003-020-0756-0
Noam Mamet 1, 2 , Yaniv Amir 3 , Erez Lavi 3 , Liron Bassali 1 , Gil Harari 1 , Itai Rusinek 1 , Nir Skalka 3 , Elinor Debby 3 , Mor Greenberg 1 , Adva Zamir 1 , Anastasia Paz 3 , Neria Reiss 3 , Gil Loewenthal 1 , Irit Avivi 4 , Avichai Shimoni 5 , Guy Neev 3 , Almogit Abu-Horowitz 1 , Ido Bachelet 1
Affiliation  

Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for exerting specific and selective biological responses in target cells. The process operates without a priori target knowledge (mutations, biomarkers, etc). We report the discovery of oligonucleotides with direct, selective cytotoxicity towards cell lines, as well as patient-derived solid and hematological tumors. A specific oligonucleotide termed E8, induced selective apoptosis in triple-negative breast cancer (TNBC) cells. Polyethylene glycol-modified E8 exhibited favorable biodistribution in animals, persisting in tumors up to 48-hours after injection. E8 inhibited tumors by 50% within 10 days of treatment in patient-derived xenograft mice, and was effective in ex vivo organ cultures from chemotherapy-resistant TNBC patients. These findings highlight a drug discovery model which is target-tailored and on-demand.

中文翻译:

通过响应定向的体外进化发现具有杀伤力的DNA寡核苷酸。

药物针对可变的和不断发展的疾病无效,以及由于选择性差而产生的不利影响,对药物开发提出了挑战。我们描述了一个强大的平台,可以解决这些限制。该平台能够快速发现体外进化出的DNA寡核苷酸,以在靶细胞中发挥特异性和选择性的生物反应。该过程在没有先验目标知识(突变,生物标记等)的情况下运行。我们报道了对细胞系以及患者源性实体和血液肿瘤具有直接,选择性细胞毒性的寡核苷酸的发现。一种称为E8的特定寡核苷酸在三阴性乳腺癌(TNBC)细胞中诱导选择性凋亡。聚乙二醇修饰的E8在动物中表现出良好的生物分布,并在注射后长达48小时内持续存在于肿瘤中。在源自患者的异种移植小鼠中,E8在治疗后的10天内可将肿瘤抑制50%,并且在对化疗耐药的TNBC患者的离体器官培养中有效。这些发现突出了针对目标和需求的药物发现模型。
更新日期:2020-01-15
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