Preclinical evaluation of sorafenib-eluting stent for suppression of human cholangiocarcinoma cells

Abstract

Background: Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. In this study, we prepared sorafenib-loaded biliary stents for potential application as drug-delivery systems for localized treatment of extrahepatic cholangiocarcinoma. Methods: A sorafenib-coated metal stent was prepared using an electrospray system with the aid of poly(ε-caprolactone) (PCL), and then its anticancer activity was investigated using human cholangiocellular carcinoma (HuCC)-T1 cells in vitro and a mouse tumor xenograft model in vivo. Anticancer activity of sorafenib against HuCC-T1 cells was evaluated by the proliferation test, matrix metalloproteinase (MMP) activity, cancer cell invasion, and angiogenesis assay in vitro and in vivo. Results: The drug-release study showed that the increased drug content on the PCL film induced a faster drug-release rate. The growth of cancer cells on the sorafenib-loaded PCL film surfaces decreased in a dose-dependent manner. MMP-2 expression of HuCC-T1 cells gradually decreased according to sorafenib concentration. Furthermore, cancer cell invasion and tube formation of human umbilical vein endothelial cells significantly decreased at sorafenib concentrations higher than 10 mM. In the mouse tumor xenograft model with HuCC-T1 cells, sorafenib-eluting PCL films significantly inhibited the growth of tumor mass and induced apoptosis of tumor cells. Various molecular signals, such as B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter, Bcl-x, caspase-3, cleaved caspase-3, Fas, signal transducer and activator of transcription 5, extracellular signal-regulated kinases, MMP-9 and pan-janus kinase/stress-activated protein kinase 1, indicated that apoptosis, inhibition of growth and invasion was cleared on sorafenibeluting PCL films. Conclusion: These sorafenib-loaded PCL films are effective in inhibiting angiogenesis, proliferation and invasion of cancer cells. We suggest that sorafenib-loaded PCL film is a promising candidate for the local treatment of cholangiocarcinoma.

Feasibility and efficacy evaluation of metallic biliary stents eluting gemcitabine and cisplatin for extrahepatic cholangiocarcinoma

“…DES is a promising therapy, and its effective design realizes the dual function of biliary drainage and local chemotherapy in malignant biliary obstructions. Relevant studies have been published, including those on esophageal cancer[ 24 , 25 ], colorectal cancer[ 26 , 27 ], and bile duct cancer[ 6 , 9 - 12 , 15 , 28 - 30 ]. Most of the biliary stents used in earlier studies were paclitaxel-eluted stents, and there seemed to be no improvement in the duration of stent patency or survival time compared to unloaded stents in several prospective pilot studies[ 10 , 12 ].…”

“…However, these studies still demonstrated the safety and feasibility of the application of DESs in patients with ECC. DESs loaded with other antitumor agents, including gemcitabine[ 29 ], sorafenib[ 15 ], and vorinostat[ 30 ], have also been investigated for safety and efficacy in malignant biliary obstruction. These DESs were all single-drug-loaded stents with a simple design and lacked complete serial in vitro and in vivo data.…”

Evolutionary cancer-favoring engineered vaccinia virus for metastatic hepatocellular carcinoma

“…Different molecular alterations influence patient response, depending on the underlying risk factors and etiologies of HCCs. Therefore, it is a major challenge to identify the key molecules, receptors, or signaling pathways and to assess their relevance as potential targets [ 26 ]. Here, we propose a simple and strategic virus CVV for treating metastatic HCCs.…”

Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma

“… 9 We have also previously reported that sorafenib has anticancer activity against HuCC-T1 cells and effectively inhibited tumor growth in an animal study. 30 In light of these observations, we are attempting to find new chemotherapeutic agents for CC.…”