Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness.

Autor:	Xie Y; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA., Wang Y; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA., Li J; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Bohemica Pharmaceuticals, LLC, La Vista, NE 68128, USA., Hang Y; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA., Jaramillo L; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Bohemica Pharmaceuticals, LLC, La Vista, NE 68128, USA., Wehrkamp CJ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Phillippi MA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mohr AM; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Chen Y; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA., Talmon GA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Mott JL; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Oupický D; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Bohemica Pharmaceuticals, LLC, La Vista, NE 68128, USA.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2018 Jul 30; Vol. 8 (16), pp. 4305-4320. Date of Electronic Publication: 2018 Jul 30 (Print Publication: 2018).
DOI:	10.7150/thno.26506
Abstrakt:	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. Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
Databáze:	MEDLINE
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