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Biomaterials. 2014 Oct;35(30):8487-95. doi: 10.1016/j.biomaterials.2014.07.001. Epub 2014 Jul 17.

Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma.

Author information

1
Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
2
Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, Republic of Korea.
3
Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.
4
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.
5
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.
6
Department of Pathology, Inha University Hospital, Incheon, Republic of Korea.
7
Digestive Endoscopy Unit, Department of Surgery, Catholic University, Rome, Italy; Department of Radiology, Catholic University, Rome, Italy.
8
Digestive Disease Institute, Virginia Mason Medical Center, Seattle, USA.
9
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
10
Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium.
11
Division of Gastroenterology, Asan Medical Center, Seoul, Republic of Korea.
12
Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.

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.

KEYWORDS:

Bile duct stent; Cholangiocarcinoma; Membrane-covered self-expanding metal stent (SEMS); Pheophorbide A; Photodynamic therapy

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