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

Hadas Gibori, Shay Eliyahu, Adva Krivitsky, Dikla Ben-Shushan, Yana Epshtein, Galia Tiram, Rachel Blau, Paula Ofek, Joo Sang Lee, Eytan Ruppin, Limor Landsman, Iris Barshack, Talia Golan, Emmanuelle Merquiol, Galia Blum, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageAmerican English
Article number16
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

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