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

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

Author information

1
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
2
Department of Computer Science and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA.
3
Blavatnik School of Computer Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
4
Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
5
Department of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel.
6
Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
7
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Ein Kerem Campus, The Hebrew University, Jerusalem, Israel.
8
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. ronitsf@post.tau.ac.il.

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.

PMID:
29295989
PMCID:
PMC5750234
DOI:
10.1038/s41467-017-02283-9
[Indexed for MEDLINE]
Free PMC Article

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