Targeted Delivery of C/EBPα-saRNA by RNA Aptamers Shows Anti-tumor Effects in a Mouse Model of Advanced PDAC
Journal
Molecular Therapy - Nucleic Acids
Journal Volume
18
Pages
142-154
Date Issued
2019
Author(s)
Yoon S.
Andrikakou P.
Vasconcelos D.
Swiderski P.
Reebye V.
Sodergren M.
Habib N.
Rossi J.J.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies; it preferentially metastasizes to the liver and is the main cause of death from this disease. In previous studies, small activating RNA against CCAAT/enhancer-binding protein-α (C/EBPα-saRNA) demonstrated efficacy of PDAC in a local subcutaneous tumor model. In this study, we focused on the efficacy of C/EBPα-saRNA in advanced stage PDAC. For targeted delivery, we selected a new anti-transferrin receptor aptamer (TR14), which demonstrated a high binding affinity to target proteins. The TR14 aptamer was internalized with clathrin-mediated endocytosis, distributed in early endosome, late endosome, and lysosome subcellularly. To investigate its anti-tumor effects to advanced PDAC, we conjugated C/EBPα-saRNA to TR14. Treatment of pancreatic cancer cells with the conjugates upregulated expression of C/EBPα and its downstream target p21, and inhibited cell proliferation. For in vivo assays, we established an advanced PDAC mouse model by engrafting luciferase reporter-PANC-1 cells directly into the livers of non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After treatment of aptamer-C/EBPα conjugates, we observed significant reduction of tumor growth in this advanced PDAC mouse model. Combinational treatment of the conjugates with gemcitabine also demonstrated enhanced anti-tumor effects in advanced PDAC. This suggests that aptamer-C/EBPα conjugates could be used as an adjuvant, along with other conventional anti-cancer drugs in advanced PDAC. In conclusion, targeted delivery of C/EBPα-saRNAs by aptamers might have potential therapeutic effects in advanced PDAC. ? 2019 The Authors
Subjects
adjuvant; advanced PDAC; albumin affinity tag; anti-tumor effects; C/EBPα-saRNA; clathrin-mediated endocytosis; targeted delivery; transferrin receptor aptamer; truncation
SDGs
Other Subjects
aptamer; CCAAT enhancer binding protein alpha; clathrin; gemcitabine; protein p21; RNA; small activating RNA; tr14 aptamer; unclassified drug; advanced cancer; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer inhibition; controlled study; drug efficacy; endocytosis; endosome; female; human; human cell; in vitro study; in vivo study; lysosome; mouse; nonhuman; pancreas adenocarcinoma; priority journal; protein expression; upregulation
Publisher
Cell Press
Type
journal article