Piperlongumine-Eluting Gastrointestinal Stent Using Reactive Oxygen Species-Sensitive Nanofiber Mats for Inhibition of Cholangiocarcinoma Cells.

BACKGROUND: The aim of this study is to fabricate drug-eluting gastrointestinal (GI) stent using reactive oxygen species (ROS)-sensitive nanofiber mats for treatment of cholangiocarcinoma (CCA) cell. A ROS-producing agent, piperlongumine (PL)-incorporated nanofiber mats were investigated for drug-eluting stent (DES) application. METHODS: Selenocystamine-conjugated methoxy poly(ethylene glycol) (MePEG) was conjugated with poly(L-lactide) (PLA) to produce block copolymer (LEse block copolymer). Various ratios of poly(ε-caprolactone) (PCL) and LEse block copolymer were dissolved in organic solvent with PL, and then nanofiber mats were fabricated by electro-spinning techniques. RESULTS: The higher amount of LEse in the blend of PCL/LEse resulted in the formation of granules while PCL alone showed fine nanofiber structure. Nanofiber mats composed of PCL/LEse polymer blend showed ROS-sensitive drug release, i.e., PL release rate from nanofiber mats was accelerated in the presence of hydrogen peroxide (H2O2) while nanofiber mats of PCL alone have small changes in drug release rate, indicating that PL-incorporated nanofiber membranes have ROS responsiveness. PL itself and PL released from nanofiber mats showed almost similar anticancer activity against various CCA cells. Furthermore, PL released from nanofiber mats properly produced ROS generation and induced apoptosis of CCA cells as well as PL itself. In HuCC-T1 cell-bearing mice, PL-incorporated nanofiber mats showed improvement in anticancer activity. CONCLUSION: PL-incorporated ROS-sensitive nanofiber mats were coated onto GI stent and showed improved anticancer activity with ROS responsiveness. We suggested PL-incorporated ROS-sensitive nanofiber mats as a promising candidate for local treatment of CCA cells.

Vorinostat-eluting poly(DL-lactide-co-glycolide) nanofiber-coated stent for inhibition of cholangiocarcinoma cells.

PURPOSE: The aim of this study was to fabricate a vorinostat (Zolinza™)-eluting nanofiber membrane-coated gastrointestinal (GI) stent and to study its antitumor activity against cholangiocarcinoma (CCA) cells in vitro and in vivo. METHODS: Vorinostat and poly(DL-lactide-co-glycolide) dissolved in an organic solvent was sprayed onto a GI stent to make a nanofiber-coated stent using an electro-spinning machine. Intact vorinostat and vorinostat released from nanofibers was used to assess anticancer activity in vitro against various CCA cells. The antitumor activity of the vorinostat-eluting nanofiber membrane-coated stent was evaluated using HuCC-T1 bearing mice. RESULTS: A vorinostat-incorporated polymer nanofiber membrane was formed on the surface of the GI stent. Vorinostat was continuously released from the nanofiber membrane over 10 days, and its release rate was higher in cell culture media than in phosphate-buffered saline. Released vorinostat showed similar anticancer activity against various CCA cells in vitro compared to that of vorinostat. Like vorinostat, vorinostat released from nanofibers induced acetylation of histone H4 and inhibited histone deacetylases 1⋅3⋅4/5/7 expression in vitro and in vivo. Furthermore, vorinostat nanofibers showed a higher tumor growth inhibition rate in HuCC-T1 bearing mice than vorinostat injections. CONCLUSION: Vorinostat-eluting nanofiber membranes showed significant antitumor activity against CCA cells in vitro and in vivo. We suggest the vorinostat nanofiber-coated stent may be a promising candidate for CCA treatment.

Simple nanophotosensitizer fabrication using water-soluble chitosan for photodynamic therapy in gastrointestinal cancer cells.

The polysaccharide chitosan has abundant cationic amine groups, and can form ion-complexes with anionic molecules such as the strong photosensitizer chlorin e6 (Ce6). In this study, water-soluble chitosan (WSC) was used to fabricate Ce6-incorporated nanophotosensitizers (Abbreviated as ChitoCe6 nanophotosensitizer) via a self-assembling process. This was accomplished by dissolving WSC in pure water and then directly mixing the solution with solid Ce6 causing ion complex formation between WSC and Ce6. The resulting nanophotosensitizer was spherical in shape and had a particle size of less than 300nm. The photodynamic effect of ChitoCe6 nanophotosensitizer was evaluated using gastrointestinal (GI) cancer cells. At in vitro study using SNU478 cholangiocarcinoma cells, ChitoCe6 nanophotosensitizer showed improved Ce6 uptake by tumor cells, reactive oxygen species production, and cellular phototoxicity. An in vivo study using SNU478-bearing nude mice showed that the ChitoCe6 nanophotosensitizer efficiently accumulated in the tumor tissue and inhibited tumor growth more than treatment with Ce6 alone. Furthermore, ChitoCe6 nanophotosensitizer was also efficiently absorbed through tissue layers in an ex vivo study using porcine bile duct explants. ChitoCe6 nanophotosensitizer showed enhanced photosensitivity and photodynamic effects against cancer cells in vitro and in vivo. We present ChitoCe6 nanophotosensitizer as a promising candidate for photodynamic therapy of GI cancer.