Targeting and Regulating of an Oncogene via Nanovector Delivery of MicroRNA using Patient-Derived Xenografts.

Shuyang Sun;Yilong Wang;Rong Zhou;Zicheng Deng;Yong Han;Xiao Han;Wenjie Tao;Zi Yang;Chaoji Shi;Duo Hong;Jiang Li;Donglu Shi;Zhiyuan Zhang

期刊论文

10.7150/thno.16357

SCIE

Theranostics

7#3

2017/1/15

677#693

677#693

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.

mesoporous nanovector, oncogene, microRNA, Patient-Derived Xenografts, precision medicine.

miR-324-5p/PTPN18/c-Met/FZD8信号轴作为口腔鳞癌干细胞治疗靶点的实验研究