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J Control Release. 2015 Oct 28;216:93-102. doi: 10.1016/j.jconrel.2015.08.022. Epub 2015 Aug 14.

Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT).

Author information

1
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain.
2
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
3
Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL, Salamanca, Spain.
4
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastián, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
5
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain. Electronic address: jjgmarin@usal.es.

Abstract

Novel antitumour drugs, such as cationic tyrosine kinase inhibitors, are useful in many types of cancer but not in others, such as cholangiocarcinoma (CCA), where their uptake through specific membrane transporters, such as OCT1, is very poor. Here we have investigated the usefulness of targeting cytostatic bile acid derivatives to enhance the delivery of chemotherapy to tumours expressing the bile acid transporter ASBT and whether this is the case for CCA. The analysis of paired samples of CCA and adjacent non-tumour tissue collected from human (n=15) and rat (n=29) CCA revealed that ASBT expression was preserved. Moreover, ASBT was expressed, although at different levels, in human and rat CCA cell lines. Both cells in vitro and rat tumours in vivo were able to carry out efficient uptake of bile acid derivatives. Using Bamet-UD2 (cisplatin-ursodeoxycholate conjugate) as a model ASBT-targeted drug, in vitro and in vivo antiproliferative activity was evaluated. ASBT expression enhanced the sensitivity to Bamet-UD2, but not to cisplatin, in vitro. In nude mice, Bamet-UD2 (more than cisplatin) inhibited the growth of human colon adenocarcinoma tumours with induced stable expression of ASBT. As compared with cisplatin, administration of Bamet-UD2 to rats with CCA resulted in an efficient liver and tumour uptake but low exposure of extrahepatic tissues to the drug. Consequently, signs of liver/renal toxicity were absent in animals treated with Bamet-UD2. In conclusion, endogenous or induced ASBT expression may be useful in pharmacological strategies to treat enterohepatic tumours based on the use of cytostatic bile acid derivatives.

KEYWORDS:

Biliary tumour; Cancer; Chemoresistance; Chemotherapy; Cisplatin; Drug targeting; Ursodeoxycholic acid

PMID:
26278512
DOI:
10.1016/j.jconrel.2015.08.022
[Indexed for MEDLINE]

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