Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth in Vivo
Journal
Molecular Therapy
Journal Volume
24
Journal Issue
6
Pages
1106-1116
Date Issued
2016
Author(s)
Yoon S.
Reebye V.
Mintz P.
S?trom P.
Reccia I.
Swiderski P.
Armstrong B.
Jozwiak A.
Spalding D.
Jiao L.
Habib N.
Rossi J.J.
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.
SDGs
Other Subjects
2' fluoropyrimidine RNA aptamer; aptamer; CCAAT enhancer binding protein alpha; molecular therapy agent; protein p21; small activating RNA; unclassified drug; aptamer; CCAAT enhancer binding protein alpha; RNA; animal experiment; animal model; Article; cancer inhibition; cell proliferation; controlled study; human; human tissue; immunohistochemistry; in vitro study; in vivo study; internalization; major clinical study; mitosis inhibition; molecularly targeted therapy; mouse; nonhuman; pancreas adenocarcinoma; protein expression; systematic evolution of ligands by exponential enrichment aptamer technique; tissue distribution; tumor growth; tumor volume; tumor xenograft; animal; antibody specificity; Carcinoma, Pancreatic Ductal; drug effects; drug resistance; drug screening; genetics; Pancreatic Neoplasms; treatment outcome; tumor cell line; upregulation; Animals; Aptamers, Nucleotide; Carcinoma, Pancreatic Ductal; CCAAT-Enhancer-Binding Protein-alpha; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Mice; Organ Specificity; Pancreatic Neoplasms; RNA; Treatment Outcome; Up-Regulation; Xenograft Model Antitumor Assays
Publisher
Nature Publishing Group
Type
journal article