Abstract
MiR‐101, an important tumor‐suppressive microRNA (miRNA) in hepatocellular carcinoma (HCC), has been affirmed significantly downregulated in HCC and participated in promoting apoptosis, decreasing proliferation and invasiveness of HCC cells, as well as increasing sensitivity of chemotherapeutic drug. However, miR‐101‐based combination therapies with doxorubicin (DOX) are not reported yet. Recently, nanomaterials‐based approaches, especially liposome formulations, have been approved for clinical use and seem to provide a great opportunity to codeliver therapeutic agents for cancer therapy. In this study, we have successfully prepared liposome (L) nanoparticles to efficiently deliver miR‐101 and DOX to HCC cells simultaneously. The effects of codelivery system miR‐101/doxorubicin liposome (miR‐101/DOX‐L) on tumor malignant phenotypes of HCC cells were evaluated through analyzing cell proliferation, colony formation, cell migration, cell invasion, cell apoptosis assay, and the expression of related genes. In subcutaneous xenografts developed by HCC cells, the inhibition of tumor growth was analyzed through gross morphology, growth curve, proliferation marker Ki‐67, apoptosis signals, and the expression of related genes. These experiments demonstrated that miR‐101/DOX‐L inhibited tumor properties of liver cancer cells in vitro and in vivo through targeting correlative genes by combinatory role of miR‐101 and DOX. In conclusion, our results indicated that liposome nanoparticle is a reliable delivery strategy to codeliver miR‐101 and DOX simultaneously, and miR‐101‐ and DOX‐based combination therapy can result in significant synergetic antitumor effects in vivo and vitro.
Highlights
Hepatocellular carcinoma (HCC), as the major form of primary liver cancer, is a worldwide malignancy
DOX-L and miR-1 01/DOX-L were synthesized as described in the Materials and Methods section and were characterized by dynamic light scattering (DLS)
By DLS detection, the average particle sizes of liposome (L), DOX-L, and miR-101/DOX-L were 119.4, 121.8, and 159.8 nm, respectively. This indicated that miRNA binding to DOX-L increased the diameter of DOX-L by about 40 nm
Summary
Hepatocellular carcinoma (HCC), as the major form of primary liver cancer, is a worldwide malignancy. Dysregulation of miRNAs appears to play fundamental roles in many cancers, and replacement of downregulated miRNAs in tumor cells may result in positive therapeutic responses. Their small size makes them attractive for drug development. Researches recently reported that overexpression of miR-101 could completely suppress liver tumor formation induced by c-Myc and AKT/Ras oncogenes [13]. These studies together strongly suggested an important tumor suppressor role of miR-101 and highlighted the attractive therapeutic potential of miR-101 in HCC
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