EWS fli-1 antisense nanocapsules inhibits ewing sarcoma-related tumor in mice

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• Ewing's sarcoma and primitive neuroectodermal tumor (PNET) are aggressive cancers characterized by the EWS Fli-1 fusion gene in 90% of cases.
• Targeting the EWS Fli-1 fusion gene is a key strategy for treating these tumors.

Purpose of the Study:

• To develop and evaluate polyisobutylcyanoacrylate nanocapsules for the in vivo delivery of phosphorothioate oligonucleotides (ODN) targeting the EWS Fli-1 chimeric RNA.
• To assess the efficacy of these nanocapsules in inhibiting Ewing sarcoma-related tumors in a mouse model.

Main Methods:

• Encapsulation of phosphorothioate oligonucleotides (ODN) against EWS Fli-1 chimeric RNA into polyisobutylcyanoacrylate nanocapsules with an aqueous core.
• Characterization of ODN release kinetics in serum medium, demonstrating biphasic release due to different nanocapsule types.
• Evaluation of nanocapsule protection against serum degradation of oligonucleotides.
• Assessment of tumor inhibition in mice following intratumoral injection of ODN-loaded nanocapsules.

Main Results:

• High encapsulation efficiency of ODN against EWS Fli-1 was achieved.
• Nanocapsules exhibited biphasic ODN release, indicating controlled delivery kinetics.
• The nanocapsules protected ODN from degradation in serum.
• Intratumoral injection of ODN nanocapsules resulted in significant inhibition of Ewing sarcoma-related tumors in mice at a low cumulative dose (14.4 nanomoles).

Conclusions:

• Polyisobutylcyanoacrylate nanocapsules are effective non-viral vectors for delivering therapeutic oligonucleotides.
• This nanocarrier system demonstrates significant potential for in vivo administration of ODN for cancer therapy, specifically for Ewing sarcoma and PNET.
• The controlled release and protective properties of the nanocapsules contribute to their therapeutic efficacy.