Targeted delivery of C/EBPα -saRNA by pancreatic ductal adenocarcinoma-specific RNA aptamers inhibits tumor growth in vivo
File(s)
Author(s)
Type
Journal Article
Abstract
The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.
Date Issued
2016-04-12
Date Acceptance
2016-03-06
Citation
Molecular Therapy, 2016, 24 (6), pp.1106-1116
ISSN
1525-0024
Publisher
Nature Publishing Group
Start Page
1106
End Page
1116
Journal / Book Title
Molecular Therapy
Volume
24
Issue
6
Copyright Statement
This work is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 4.0
International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative
Commons license, users will need to obtain permission from
the license holder to reproduce the material. To view a copy
of this license, visit http://creativecommons.org/licenses/bync-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0
International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative
Commons license, users will need to obtain permission from
the license holder to reproduce the material. To view a copy
of this license, visit http://creativecommons.org/licenses/bync-sa/4.0/
Identifier
PII: mt201660
Subjects
Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
VITRO SELECTION
SYSTEMATIC EVOLUTION
CANCER CELLS
LIGANDS
RESECTION
BINDING
PROTEIN
TRIAL
SELEX
CHEMOTHERAPY
Animals
Aptamers, Nucleotide
CCAAT-Enhancer-Binding Protein-alpha
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Humans
Mice
Organ Specificity
Pancreatic Neoplasms
RNA
Treatment Outcome
Up-Regulation
Xenograft Model Antitumor Assays
Cell Line, Tumor
Animals
Humans
Mice
Carcinoma, Pancreatic Ductal
Pancreatic Neoplasms
CCAAT-Enhancer-Binding Protein-alpha
RNA
Treatment Outcome
Xenograft Model Antitumor Assays
Cell Proliferation
Organ Specificity
Up-Regulation
Drug Resistance, Neoplasm
Aptamers, Nucleotide
06 Biological Sciences
10 Technology
11 Medical and Health Sciences
Biotechnology
Publication Status
Published
Date Publish Online
2016-12-14