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.