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 and Ronit Satchi-Fainaro ()
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Hadas Gibori: Tel Aviv University
Shay Eliyahu: Tel Aviv University
Adva Krivitsky: Tel Aviv University
Dikla Ben-Shushan: Tel Aviv University
Yana Epshtein: Tel Aviv University
Galia Tiram: Tel Aviv University
Rachel Blau: Tel Aviv University
Paula Ofek: Tel Aviv University
Joo Sang Lee: University of Maryland
Eytan Ruppin: Tel Aviv University
Limor Landsman: Tel Aviv University
Iris Barshack: Sheba Medical Center
Talia Golan: Sheba Medical Center
Emmanuelle Merquiol: The Hebrew University
Galia Blum: The Hebrew University
Ronit Satchi-Fainaro: Tel Aviv University

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02283-9

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