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

详细信息    查看全文

• 作者：Elisa Lozano^a ; Maria J. Monte^a ; ^d ; Oscar Briz^a ; ^d ; Angel Herná ; ndez-Herná ; ndez^b ; Jesus M. Banales^c ; ^d ; Jose J.G. Marin^a ; ^d ; ^{jjgmarin@usal.es" class="auth_mail" title="E-mail the corresponding author} ; Rocio I.R. Macias^a ; ^d
• 关键词：ASBT ; apical sodium dependent bile acid transporter ; CCA ; cholangiocarcinoma ; CGamF ; cholylglycyl amidofluorescein ; CK-7 ; cytokeratin-7 ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; GSTpi ; placental isoform of glutathione S-transferase ; HCC ; hepatocellular carcinoma ; MDR ; multidrug resistance ; OCT1 ; organic cation transporter 1 ; TAA ; thioacetamide ; TCA ; taurocholic acid ; UDCA ; ursodeoxycholic acid
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 October 2015
• 年：2015
• 卷：216
• 期：Complete
• 页码：93-102
• 全文大小：1888 K

文摘

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.