Abstract
The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Carcinoma, Pancreatic Ductal / genetics*
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / therapy
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Drug Carriers / chemistry
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Kaplan-Meier Estimate
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Male
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Mice, Inbred C57BL
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Mice, SCID
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MicroRNAs / genetics*
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Middle Aged
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Nanostructures / chemistry
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / therapy
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Polo-Like Kinase 1
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA Interference
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RNA, Small Interfering / chemistry
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RNA, Small Interfering / genetics*
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RNAi Therapeutics / methods
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Xenograft Model Antitumor Assays / methods
Substances
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Cell Cycle Proteins
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Drug Carriers
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MIRN34 microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Protein Serine-Threonine Kinases