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Influence of the Internalization Pathway on the Efficacy of siRNA Delivery by Cationic Fluorescent Nanodiamonds in the Ewing Sarcoma Cell Model

Anna Alhaddad, Catherine Durieu, Géraldine Dantelle, Eric Le Cam, Claude Malvy, François Treussart, Jean-Rémi Bertrand, PLoS ONE 7(12): e52207

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Small interfering RNAs (siRNAs) are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors.

PLoS ONE 7(12): e52207

Acknowledgements
We thank the Imaging and Cytometry Platform team at the Gustave Roussy Institute for assistance and access to confocal microscopy facilities. We thank Franc ois Dautry, Karim Benihoud, Dragomira Majhen and SoniaBaconnaisforfruitfuldiscussions,andF.Carrel,F.Laine andP. Bergonzo for assistance with the electron beam irradiation used to prepare the fluorescent nanodiamonds. A. Alhaddad received a PhD grant from the Faculty of Pharmacy of Damas (Syria).

This work has been supported by the Pôle de Recherche et d'Enseignement Supérieur UniverSud Paris'', by a Centre National de la Recherche Scientifique (CNRS) international joint project for scientific cooperation'' grant, and by the Region Ile-de-France in the framework of C'Nano IdF. C'Nano IdF is the nanoscience competence center of Paris Region, supported by CNRS, CEA, Ministry of Higher Education and Research and Region Ile-de-France, France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

doi:10.1371/journal.pone.0052207
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