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Pharmaceutical Research

, Volume 23, Issue 5, pp 892–900 | Cite as

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

  • Nedjma Toub
  • Jean-Rémi Bertrand
  • Ali Tamaddon
  • Hind Elhamess
  • Hervé Hillaireau
  • Andrei Maksimenko
  • Jean Maccario
  • Claude Malvy
  • Elias Fattal
  • Patrick Couvreur
Research Paper

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.

Key Words

Ewing sarcoma EWS–Fli1 isobutylcyanoacrylate nanocapsules siRNA 

Notes

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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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Nedjma Toub
    • 1
    • 2
  • Jean-Rémi Bertrand
    • 2
  • Ali Tamaddon
    • 2
  • Hind Elhamess
    • 2
  • Hervé Hillaireau
    • 1
  • Andrei Maksimenko
    • 2
  • Jean Maccario
    • 3
  • Claude Malvy
    • 2
  • Elias Fattal
    • 1
  • Patrick Couvreur
    • 1
  1. 1.Laboratoire de Physicochimie, Pharmacotechnie et BiopharmacieFaculté de PharmacieChâtenay-MalabryFrance
  2. 2.Laboratoire de Vecterologie et Transfert des GènesInstitut Gustave RoussyVillejuif CedexFrance
  3. 3.Centre d' Etudes PharmaceutiquesChatenay-Malabry CedexFrance

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