An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth
An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth
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DOI：
10.1182/bloodadvances.2017004705
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发表时间：
2017-06-01
期刊：
影响因子：
7.5
通讯作者：
Zheng, Pan
中科院分区：
文献类型：
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作者：
Tanno, Toshihiko;Zhang, Peng;Zheng, Pan
传统化疗的疗效受到其毒性的限制，特别是在造血方面。在这里，我们发现miR-26 a通过靶向造血干/祖细胞（HSPC）中的促凋亡蛋白（Bak 1）在保护小鼠免受化疗诱导的骨髓抑制中起着关键作用。由于c-Kit在HSPC中以高水平表达，我们设计了含有miR-26 a模拟物和c-Kit靶向适体的microRNA-适体嵌合体，并成功地将miR-26 a递送到HSPC中以减轻59氟尿嘧啶（5-FU）和卡铂的毒性。同时，我们的计算机模拟分析揭示了miR-26 a在晚期乳腺癌中的广泛和与肿瘤相关的下调，也表明KIT在基底样乳腺癌细胞中过表达，并且这种表达与预后不良相关。重要的是，在小鼠乳腺癌模型中，miR-26 a适体在体内有效抑制肿瘤生长，并与5-FU或卡铂在癌症治疗中协同作用。因此，靶向递送miR-26 a抑制肿瘤生长，同时保护宿主免受化疗引起的骨髓抑制。
The efficacy of traditional chemotherapy is limited by its toxicity, especially with regard to hematopoiesis. Here we show that miR-26a plays a critical role in protecting mice against chemotherapy-induced myeloid suppression by targeting a proapoptotic protein (Bak1) in hematopoietic stem/progenitor cells (HSPCs). Because c-Kit is expressed at high levels in HSPCs, we designed a microRNA-aptamer chimera that contains miR-26a mimic and c-Kit-targeting aptamer and successfully delivered miR-26a into HSPCs to attenuate toxicity of 59 fluorouracil (5-FU) and carboplatin. Meanwhile, our in silico analysis revealed widespread and prognosis-associated downregulation of miR-26a in advanced breast cancer and also showed that KIT is overexpressed among basal-like breast cancer cells and that such expression is associated with poor prognosis. Importantly, the miR-26a aptamer effectively repressed tumor growth in vivo and synergized with 5-FU or carboplatin in cancer therapy in the mouse breast cancer models. Thus, targeted delivery of miR-26a suppresses tumor growth while protecting the host against myelosuppression by chemotherapy.