title: Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma.
abstract: Photodynamic therapy (PDT) is a new therapeutic approach for the palliative treatment of malignant bile duct obstruction. In this study, we designed photosensitizer-embedded self-expanding nonvascular metal stent (PDT-stent) which allows repeatable photodynamic treatment of cholangiocarcinoma without systemic injection of photosensitizer. Polymeric photosensitizer (pullulan acetate-conjugated pheophorbide A; PPA) was incorporated in self-expanding nonvascular metal stent. Residence of PPA in the stent was estimated in buffer solution and subcutaneous implantation on mouse. Photodynamic activity of PDT-stent was evaluated through laserexposure on stent-layered tumor cell lines, HCT-116 tumor-xenograft mouse models and endoscopic intervention of PDT-stent on bile duct of mini pigs. Photo-fluorescence imaging of the PDT-stent demonstrated homogeneous embedding of polymeric Pheo-A (PPA) on stent membrane. PDT-stent sustained its photodynamic activities at least for 2 month. And which implies repeatable endoscopic PDT is possible after stent emplacement. The PDT-stent after light exposure successfully generated cytotoxic singlet oxygen in the surrounding tissues, inducing apoptotic degradation of tumor cells and regression of xenograft tumors on mouse models. Endoscopic biliary in-stent photodynamic treatments on minipigs also suggested the potential efficacy of PDT-stent on cholangiocarcinoma. In vivo and in vitro studies revealed our PDT-stent, allows repeatable endoscopic biliary PDT, has the potential for the combination therapy (stent plus PDT) of cholangiocarcinoma.
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Byoung-chan
authors.initials: BC
authors.lastname: Bae
authors.affiliation: Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Su-Geun
authors.initials: SG
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.
authors.forename: Seok
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Utah-Inha DDS and Advanced Therapeutics, B-404, Meet-You-All Tower, Songdo-dong, Yeonsu-gu, Incheon, Republic of Korea; Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea; Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Don Haeng
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea. Electronic address: kna6997@catholic.ac.kr.
authors.forename: Kun
authors.initials: K
authors.lastname: Na
authors.affiliation: Department of Pathology, Inha University Hospital, Incheon, Republic of Korea.
authors.forename: Joon Mee
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Digestive Endoscopy Unit, Department of Surgery, Catholic University, Rome, Italy; Department of Radiology, Catholic University, Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Costamagna
authors.affiliation: Digestive Disease Institute, Virginia Mason Medical Center, Seattle, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kozarek
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Isayama
authors.affiliation: Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Deviere
authors.affiliation: Division of Gastroenterology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Dong Wan
authors.initials: DW
authors.lastname: Seo
authors.affiliation: Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
authors.forename: D
authors.initials: D
authors.lastname: Nageshwar Reddy
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D004724:Endoscopy; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D008670:Metals / Q000737:chemistry*; D051379:Mice; D041681:NIH 3T3 Cells; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D015607:Stents; D040521:Subcutaneous Tissue / Q000473:pathology; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D008670:Metals; D017319:Photosensitizing Agents; D011108:Polymers; D002734:Chlorophyll; C032623:pheophorbide a
keywords: Bile duct stent; Cholangiocarcinoma; Membrane-covered self-expanding metal stent (SEMS); Pheophorbide A; Photodynamic therapy