Cargando…
Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer
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 effi...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750234/ https://www.ncbi.nlm.nih.gov/pubmed/29295989 http://dx.doi.org/10.1038/s41467-017-02283-9 |
_version_ | 1783289696061751296 |
---|---|
author | Gibori, Hadas Eliyahu, Shay Krivitsky, Adva Ben-Shushan, Dikla Epshtein, Yana Tiram, Galia Blau, Rachel Ofek, Paula Lee, Joo Sang Ruppin, Eytan Landsman, Limor Barshack, Iris Golan, Talia Merquiol, Emmanuelle Blum, Galia Satchi-Fainaro, Ronit |
author_facet | Gibori, Hadas Eliyahu, Shay Krivitsky, Adva Ben-Shushan, Dikla Epshtein, Yana Tiram, Galia Blau, Rachel Ofek, Paula Lee, Joo Sang Ruppin, Eytan Landsman, Limor Barshack, Iris Golan, Talia Merquiol, Emmanuelle Blum, Galia Satchi-Fainaro, Ronit |
author_sort | Gibori, Hadas |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5750234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57502342018-01-13 Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer Gibori, Hadas Eliyahu, Shay Krivitsky, Adva Ben-Shushan, Dikla Epshtein, Yana Tiram, Galia Blau, Rachel Ofek, Paula Lee, Joo Sang Ruppin, Eytan Landsman, Limor Barshack, Iris Golan, Talia Merquiol, Emmanuelle Blum, Galia Satchi-Fainaro, Ronit Nat Commun Article 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. Nature Publishing Group UK 2018-01-02 /pmc/articles/PMC5750234/ /pubmed/29295989 http://dx.doi.org/10.1038/s41467-017-02283-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gibori, Hadas Eliyahu, Shay Krivitsky, Adva Ben-Shushan, Dikla Epshtein, Yana Tiram, Galia Blau, Rachel Ofek, Paula Lee, Joo Sang Ruppin, Eytan Landsman, Limor Barshack, Iris Golan, Talia Merquiol, Emmanuelle Blum, Galia Satchi-Fainaro, Ronit Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title | Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title_full | Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title_fullStr | Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title_full_unstemmed | Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title_short | Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer |
title_sort | amphiphilic nanocarrier-induced modulation of plk1 and mir-34a leads to improved therapeutic response in pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750234/ https://www.ncbi.nlm.nih.gov/pubmed/29295989 http://dx.doi.org/10.1038/s41467-017-02283-9 |
work_keys_str_mv | AT giborihadas amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT eliyahushay amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT krivitskyadva amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT benshushandikla amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT epshteinyana amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT tiramgalia amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT blaurachel amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT ofekpaula amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT leejoosang amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT ruppineytan amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT landsmanlimor amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT barshackiris amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT golantalia amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT merquiolemmanuelle amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT blumgalia amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer AT satchifainaroronit amphiphilicnanocarrierinducedmodulationofplk1andmir34aleadstoimprovedtherapeuticresponseinpancreaticcancer |