Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness.
Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness.
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DOI：
10.7150/thno.26506
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Oupický D
中科院分区：
文献类型：
--
作者：
Xie Y;Wang Y;Li J;Hang Y;Jaramillo L;Wehrkamp CJ;Phillippi MA;Mohr AM;Chen Y;Talmon GA;Mott JL;Oupický D
胆管癌（CCA）是第二常见的原发性肝脏恶性肿瘤，由于高耐药、广泛转移和缺乏有效的治疗选择，治疗效果极差。CCA进展和转移受多种生物学因素调节，包括多种miRNA和趋化因子受体CXCR 4。本研究的目的是测试聚合物CXCR 4拮抗剂（PCX）对CXCR 4的纳米阻断与缺氧诱导的miR-210的抑制相结合是否通过降低侵袭性、诱导细胞杀伤和逆转耐药性来协同增强CCA的治疗功效。方法：首先检测PCX对CCA细胞迁移的抑制作用。然后我们制备了PCX/anti-miRNA纳米颗粒，并分析了它们的miRNA递送功效和体外抗癌活性。最后，在CCA荷瘤小鼠中进行体内生物分布测定和抗癌活性研究。结果如下：我们的研究结果表明，PCX对细胞迁移具有广泛的抑制作用，有效地递送抗miR-210，并下调CCA细胞中miR-210的表达。PCX/anti-miR-210纳米颗粒组合显示出对CCA细胞的细胞毒性活性，并减少了癌症干细胞样细胞的数量。纳米颗粒逆转缺氧诱导的耐药性，并使CCA细胞对标准吉西他滨和顺铂联合治疗敏感。在CCA异种移植模型中用纳米颗粒进行全身静脉内治疗导致显著的组合抗肿瘤活性。结论：我们的研究结果支持基于PCX的纳米颗粒作为治疗性miRNA的组合CCA疗法中有前途的递送平台。
Cholangiocarcinoma (CCA) is the second most common primary liver malignancy with extremely poor therapeutic outcome due to high drug resistance, widespread metastasis and lack of effective treatment options. CCA progression and metastasis are regulated by multiple biological factors including multiple miRNAs and chemokine receptor CXCR4. The goal of this study was to test if nanotherapeutic blockade of CXCR4 by polymeric CXCR4 antagonist (PCX) combined with inhibition of hypoxia-inducible miR-210 cooperatively enhances therapeutic efficacy in CCA through reducing invasiveness, inducing cell killing, and reversing drug resistance. Methods: We first tested the activity of PCX to inhibit migration of CCA cells. We then prepared PCX/anti-miRNA nanoparticles and analyzed their miRNA delivery efficacy and anticancer activity in vitro. Finally, in vivo biodistribution assay and anticancer activity study were performed in CCA tumor-bearing mice. Results: Our results show that PCX had a broad inhibitory effect on cell migration, effectively delivered anti-miR-210, and downregulated miR-210 expression in CCA cells. Combination PCX/anti-miR-210 nanoparticles showed cytotoxic activity towards CCA cells and reduced the number of cancer stem-like cells. The nanoparticles reversed hypoxia-induced drug resistance and sensitized CCA cells to standard gemcitabine and cisplatin combination treatment. Systemic intravenous treatment with the nanoparticles in a CCA xenograft model resulted in prominent combined antitumor activity. Conclusion: Our findings support PCX-based nanoparticles as a promising delivery platform of therapeutic miRNA in combination CCA therapies.