Related Experiment Video
Updated: Jun 20, 2026
Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model
Published on: September 27, 2024
Antitumor vectorized oligonucleotides in a model of ewing sarcoma: unexpected role of nanoparticles
Hind Elhamess1, Jean-Rémi Bertrand, Jean Maccario
1Laboratoire de Vectorologie et Transfert des Gènes, Institut Gustave Roussy, UMR CNRS 8121, 39 rue Camille Desmoulins, Villejuif Cedex 94805, France. helhamess@igr.fr
Abstract:
Oligonucleotides (ONs) such as antisense oligonucleotides (AS-ON) and siRNAs are used as experimental tools to study gene function and are currently being tested in clinical trials for use as therapeutic anticancer agents. However, their therapeutic use has been limited by their low physiological stability and their slow cellular uptake. The systemic delivery of sequence-specific AS-ON targeting the EWS/FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of Ewing's sarcoma. The nonviral delivery system uses a poly-iso-hexyl-cyanoacrylate (PIHCA)-containing polycation (chitosan) to bind and protect the AS-ON. No antitumor effect is observed using a control oligonucleotide sequence. We found here that injection of the free AS-ON stimulates tumor growth independently of its sequence and that this stimulation is abolished in the presence of nanosphere-chitosan, which exerts with the oligonucleotides a specific inhibitory effect on tumor growth. The stimulation of tumor growth is likely to be due to a polyanionic effect; indeed, a similar stimulatory response is observed upon treatment with dextran sulfate and heparin in vivo. These results suggest that ON loaded onto nanosphere-chitosan provides efficient and tumor-specific delivery, and provides protection against a polyanionic secondary effect.
Insights
Targeted delivery of antisense oligonucleotides (AS-ON) using nanosphere-chitosan inhibits Ewing's sarcoma growth. This system overcomes limitations of free AS-ON, preventing tumor-stimulating polyanionic effects.
Area of Science:
- * Nanomedicine and Gene Therapy
- * Cancer Research
- * Drug Delivery Systems
Background:
- * Oligonucleotides (ONs), including antisense oligonucleotides (AS-ON) and siRNAs, are valuable research tools and potential anticancer therapeutics.
- * Therapeutic application of ONs is hindered by poor stability and cellular uptake.
- * Effective delivery systems are crucial for harnessing the potential of ONs in cancer treatment.
Purpose of the Study:
- * To evaluate a targeted, nonviral delivery system for sequence-specific AS-ON in Ewing's sarcoma.
- * To investigate the impact of the delivery system on AS-ON stability, cellular uptake, and antitumor efficacy.
- * To elucidate the mechanisms underlying AS-ON efficacy and potential side effects.
Main Methods:
- * Development of a nonviral delivery system using poly-iso-hexyl-cyanoacrylate (PIHCA)-chitosan nanospheres to encapsulate AS-ON.
- * Systemic administration of AS-ON targeting EWS/FLI1 in a murine model of Ewing's sarcoma.
- * Comparison of tumor growth inhibition between sequence-specific AS-ON, control ON, and free AS-ON.
- * Assessment of tumor growth stimulation by free ON and polyanions like dextran sulfate and heparin.
Main Results:
- * Systemic delivery of EWS/FLI1-targeting AS-ON via PIHCA-chitosan nanospheres significantly inhibited tumor growth.
- * Free AS-ON, regardless of sequence, stimulated tumor growth, an effect attributed to a polyanionic effect.
- * The nanosphere-chitosan delivery system protected AS-ON and abolished the tumor-stimulating effect of free ON.
- * Control oligonucleotide sequences showed no antitumor effect.
Conclusions:
- * Nanosphere-chitosan effectively delivers AS-ON, providing protection and enabling tumor-specific delivery.
- * The delivery system overcomes the limitations of free ON, preventing unintended tumor stimulation.
- * This targeted approach shows promise for developing effective oligonucleotide-based cancer therapies.
