title: Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Sorah
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Huang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Vikash
authors.initials: V
authors.lastname: Reebye
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Mintz
authors.affiliation: Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Tien
authors.affiliation: Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan.
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Sætrom
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Reccia
authors.affiliation: Shared Resource-DNA/RNA Peptide, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.affiliation: Light Microscopy Core, City of Hope, Duarte, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Armstrong
authors.affiliation: Shared Resource-DNA/RNA Peptide, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jozwiak
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Spalding
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Long
authors.initials: L
authors.lastname: Jiao
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Nagy
authors.initials: N
authors.lastname: Habib
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, City of Hope, Duarte, California, USA. Electronic address: jrossi@coh.org.
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D012313:RNA / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D052157:Aptamers, Nucleotide; D022763:CCAAT-Enhancer-Binding Protein-alpha; D012313:RNA