Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo
| Autor: | Pål Sætrom, Agnieszka Jozwiak, Paul J. Mintz, John J. Rossi, Long R. Jiao, Yu-Wen Tien, Sorah Yoon, Brian Armstrong, Piotr Swiderski, Nagy A. Habib, Hong-Shiee Lai, Isabella Reccia, Kai-Wen Huang, Vikash Reebye, Duncan Spalding |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system diseases Cell PROTEIN Research & Experimental Medicine Mice 10 Technology Targeted Molecular Therapy BINDING Drug Discovery 11 Medical and Health Sciences Genetics & Heredity SELEX CHEMOTHERAPY Aptamers Nucleotide Up-Regulation Treatment Outcome medicine.anatomical_structure Medicine Research & Experimental Organ Specificity Molecular Medicine LIGANDS TRIAL Corrigendum Life Sciences & Biomedicine Carcinoma Pancreatic Ductal Biotechnology RESECTION Aptamer Biology SYSTEMATIC EVOLUTION 03 medical and health sciences Downregulation and upregulation Cell Line Tumor CCAAT-Enhancer-Binding Protein-alpha Genetics medicine Animals Humans CANCER CELLS Molecular Biology Cell Proliferation Pharmacology Science & Technology Cell growth RNA 06 Biological Sciences Xenograft Model Antitumor Assays Molecular biology Pancreatic Neoplasms 030104 developmental biology Biotechnology & Applied Microbiology Drug Resistance Neoplasm Cancer cell VITRO SELECTION Systematic evolution of ligands by exponential enrichment |
| Zdroj: | Molecular Therapy. 24:1106-1116 |
| ISSN: | 1525-0016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|