title: 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 sorafenib-eluting PCL films.
  
  
  CONCLUSIONS
  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.
authors: National Research and Development Center for Hepatobiliary Cancer, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, South Korea.
authors: Do Hyung
authors: DH
authors: Kim
authors: Young-Il
authors: YI
authors: Jeong
authors: Chung-Wook
authors: CW
authors: Chung
authors: Cy Hyun
authors: CH
authors: Kim
authors: Tae Won
authors: TW
authors: Kwak
authors: Hye Myeong
authors: HM
authors: Lee
authors: Dae Hwan
authors: DH
authors: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma; D004353:Drug Evaluation, Preclinical; D054855:Drug-Eluting Stents; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011091:Polyesters; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011091:Polyesters; C016240:polycaprolactone; D009536:Niacinamide; D000077157:Sorafenib; D020778:Matrix Metalloproteinase 2
keywords: angiogenesis; biliary stent; human cholangiocarcinoma cells; polycaprolactone; sorafenib
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