Targeting and Regulating of an Oncogene via Nanovector Delivery of MicroRNA using Patient-Derived Xenografts.
Targeting and Regulating of an Oncogene via Nanovector Delivery of MicroRNA using Patient-Derived Xenografts.
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使用患者来源的异种移植物通过纳米载体递送 MicroRNA 来靶向和调节癌基因。
DOI：
10.7150/thno.16357
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Sun S;Wang Y;Zhou R;Deng Z;Han Y;Han X;Tao W;Yang Z;Shi C;Hong D;Li J;Shi D;Zhang Z
在精准癌症纳米医学中，关键是识别导致肿瘤发生的癌基因，在此基础上，这些基因驱动因子可以分别受到纳米载体导向、癌基因靶向的 microRNA (miRNA) 的特异性调控，从而抑制肿瘤。成纤维细胞生长因子受体 3 (FGFR3) 就是这样一种癌基因。通过基因组测序鉴定出含有 FGFR3 基因组改变的分子肿瘤亚型，并将其称为 FGFR3 驱动的肿瘤。这种基于基因组学的肿瘤分类为开发 FGFR3 靶向 miRNA 替代疗法治疗 FGFR3 基因异常患者提供了进一步的理论依据。然而，由于缺乏有效的递送载体，成功的 miRNA 疗法受到阻碍。在这项研究中，开发了一种用于 microRNA-100 (miR-100) 介导的 FGFR3 调节的纳米载体。纳米载体由与三元聚合物缀合的介孔磁性簇组成，可有效实现 miRNA 体内递送。由于聚阳离子聚合物功能化的介孔结构，纳米载体的 miRNA 负载能力很高，表现出优异的肿瘤细胞转染和 pH 敏感的 miRNA 释放。将 miR-100 递送至癌细胞可有效下调 FGFR3 的表达，抑制细胞增殖，并在体外诱导细胞凋亡。患者来源的异种移植物 (PDX) 用于评估 miRNA 递送在 FGFR3 驱动的肿瘤中的功效。值得注意的是，在 FGFR3 驱动的肿瘤和没有 FGFR3 基因组改变的肿瘤之间观察到鲜明的对比。只有 FGFR3 驱动的 PDX 会通过 miR-100 的传递而受到显着抑制，而非 FGFR3 驱动的 PDX 则不受影响，这显示出精准癌症纳米医学的前景。
In precision cancer nanomedicine, the key is to identify the oncogenes that are responsible for tumorigenesis, based on which these genetic drivers can be each specifically regulated by a nanovector-directed, oncogene-targeted microRNA (miRNA) for tumor suppression. Fibroblast Growth Factor Receptor 3 (FGFR3) is such an oncogene. The molecular tumor-subtype harboring FGFR3 genomic alteration has been identified via genomic sequencing and referred to as the FGFR3-driven tumors. This genomics-based tumor classification provides further rationale for the development of the FGFR3-targeted miRNA replacement therapy in treating patients with FGFR3 gene abnormity. However, successful miRNA therapy has been hampered by lacking of an efficient delivery vehicle. In this study, a nanovector is developed for microRNA-100 (miR-100) -mediated FGFR3 regulation. The nanovector is composed of the mesoporous magnetic clusters that are conjugated with ternary polymers for efficient miRNA in-vivo delivery. The miRNA-loading capacity of the nanovector is found to be high due to the polycation polymer functionalized mesoporous structure, showing excellent tumor cell transfection and pH-sensitive miRNA release. Delivery of miR-100 to cancer cells effectively down-regulates the expression of FGFR3, inhibits cell proliferation, and induces cell apoptosis in vitro. Patient-derived xenografts (PDXs) are used to evaluate the efficacy of miRNA delivery in the FGFR3-driven tumors. Notably, sharp contrasts are observed between the FGFR3-driven tumors and those without FGFR3 genomic alteration. Only the FGFR3-driven PDXs are significantly inhibited via miR-100 delivery while the non-FGFR3-driven PDXs are not affected, showing promise of precision cancer nanomedicine.