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Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma
Nedjma Toub1, Jean-Rémi Bertrand, Ali Tamaddon
1Laboratoire de Physicochimie, Pharmacotechnie et Biopharmacie, Faculté de Pharmacie, UMR CNRS 8612, 92286, Châtenay-Malabry, France.
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.
Insights
Nanocapsules effectively deliver small interfering RNAs (siRNAs) to target the EWS-Fli1 oncogene, inhibiting Ewing sarcoma tumor growth in vivo. This offers a promising new therapeutic strategy for cancers driven by fusion oncogenes.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Ewing sarcoma is driven by the EWS-Fli1 fusion oncogene.
- Targeting the unique EWS-Fli1 mRNA presents a potential therapeutic strategy.
- Developing efficient delivery systems for small interfering RNAs (siRNAs) is crucial.
Purpose of the Study:
- To evaluate the efficacy of siRNAs targeting the EWS-Fli1 transcript.
- To assess the role of polyisobutylcyanoacrylate nanocapsules in siRNA delivery.
- To investigate the in vitro and in vivo therapeutic potential of siRNA-loaded nanocapsules.
Main Methods:
- siRNAs targeting EWS-Fli1 were synthesized.
- Nanocapsules were formulated using polyisobutylcyanoacrylate.
- Intracellular penetration was assessed using confocal microscopy in NIH/3T3 EWS-Fli1 cells.
- In vivo efficacy was tested on mice xenografted with EWS-Fli1-expressing tumors.
Main Results:
- Nanocapsules enhanced siRNA intracellular penetration, with primarily cytoplasmic localization.
- Intratumoral injection of nanocapsule-loaded siRNA inhibited tumor growth in a dose-dependent manner.
- Specific inhibition of the EWS-Fli1 oncogene was observed.
Conclusions:
- Biodegradable siRNA-loaded nanocapsules are effective in delivering therapeutic payloads.
- This approach demonstrates significant potential for treating Ewing sarcoma and other cancers with fusion oncogenes.
- Nanocapsule-mediated siRNA delivery represents a promising avenue for targeted cancer therapy.
