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Efficacy of siRNA Nanocapsules Targeted Against the EWS–Fli1 Oncogene in Ewing Sarcoma

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Abstract

The EWS–Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS–Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS–Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivo on a mice xenografted EWS–Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS–Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.

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Acknowledgments

We thank Mr. Jalil Abdelali and Mrs. Monique Stanciu (G. Roussy Institute) for excellent technical assistance and Mrs. Ghislaine Frébourg (UMR CNRS 7138) for electronic microscopy experiments. N. Toub is supported by a fellowship from La Ligue Nationale Contre le Cancer. This work was supported by the Association de Recherche sur le Cancer (grant no. 4310), Fondation de l'Avenir, and the European grant PROTHETS (contract no. LSHC-CT-2004 5033036).

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Authors and Affiliations

  1. Laboratoire de Physicochimie, Pharmacotechnie et Biopharmacie, Faculté de Pharmacie, UMR CNRS 8612, 92286, Châtenay-Malabry, France

    Nedjma Toub, Hervé Hillaireau, Elias Fattal & Patrick Couvreur

  2. Laboratoire de Vecterologie et Transfert des Gènes, Institut Gustave Roussy, UMR CNRS 8121, 39, rue Camille Desmoulins, 94805, Villejuif Cedex, France

    Nedjma Toub, Jean-Rémi Bertrand, Ali Tamaddon, Hind Elhamess, Andrei Maksimenko & Claude Malvy

  3. Centre d' Etudes Pharmaceutiques, 12 roe J.B. Clément, 92296, Chatenay-Malabry Cedex, France

    Jean Maccario

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  1. Nedjma Toub
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Correspondence to Claude Malvy.

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Toub, N., Bertrand, JR., Tamaddon, A. et al. Efficacy of siRNA Nanocapsules Targeted Against the EWS–Fli1 Oncogene in Ewing Sarcoma. Pharm Res 23, 892–900 (2006). https://doi.org/10.1007/s11095-006-9901-9

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