Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Nat Commun. 2018 Jan 2;9(1):16. doi: 10.1038/s41467-017-02283-9.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / therapy
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Drug Carriers / chemistry
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Kaplan-Meier Estimate
  • Male
  • Mice, Inbred C57BL
  • Mice, SCID
  • MicroRNAs / genetics*
  • Middle Aged
  • Nanostructures / chemistry
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / therapy
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics*
  • RNAi Therapeutics / methods
  • Xenograft Model Antitumor Assays / methods

Substances

  • Cell Cycle Proteins
  • Drug Carriers
  • MIRN34 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1