Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma

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.