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Stimuli-Responsive Peptide/siRNA Nanoparticles as a Radiation Sensitizer for Glioblastoma Treatment by Co-Inhibiting
Bohong Cen1,2, Jian Zhang1, Xinghua Pan3
1Department of Radiation Oncology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China.
Purpose:
To develop a novel approach for increasing radiosensitivity in glioblastoma (GBM) by using targeted nanoparticles to deliver siRNA aimed at silencing the EGFR and RELA/P65 genes, which are implicated in radioresistance.
Patients And Methods:
We engineered biodegradable, tumor-targeted, self-assembled, and stimuli-responsive peptide nanoparticles for efficient siRNA delivery. We evaluated the nanoparticles' ability to induce gene silencing and enhance DNA damage under radiation in vitro and in vivo. The nanoparticles were designed to exhibit pH-responsive endosomal escape and αvβ3 integrin targeting, allowing for preferential accumulation at tumor sites and traversal of the blood-brain tumor barrier.
Results:
The application of these nanoparticles resulted in significant gene silencing, increased apoptosis, and decreased cell viability. The treatment impaired DNA repair mechanisms, thereby enhancing radiosensitivity in GBM cells. In a GBM mouse model, the combination of nanoparticle treatment with radiotherapy notably prolonged survival without apparent toxicity.
Conclusion:
Our findings suggest that nanoparticle-mediated dual gene silencing can effectively overcome GBM radioresistance. This strategy has the potential to improve clinical outcomes in GBM treatment, proposing a promising therapeutic avenue for this challenging malignancy.
Insights
Targeted nanoparticles deliver siRNA to silence EGFR and RELA/P65 genes, enhancing glioblastoma radiosensitivity. This novel approach significantly improved survival in preclinical models without toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Glioblastoma (GBM) exhibits significant radioresistance, limiting the efficacy of standard radiotherapy.
- Specific genes, including EGFR and RELA/P65, are known to contribute to GBM's resistance to radiation therapy.
Purpose of the Study:
- To develop and evaluate targeted nanoparticles for delivering siRNA to silence EGFR and RELA/P65 genes in glioblastoma.
- To enhance the radiosensitivity of glioblastoma cells using this novel nanoparticle-mediated gene silencing approach.
Main Methods:
- Engineered biodegradable, tumor-targeted, stimuli-responsive peptide nanoparticles for efficient siRNA delivery.
- Utilized pH-responsive endosomal escape and αvβ3 integrin targeting for enhanced tumor accumulation and blood-brain tumor barrier traversal.
- Assessed nanoparticle efficacy in inducing gene silencing, enhancing DNA damage, and promoting apoptosis in vitro and in vivo.
Main Results:
- Demonstrated significant gene silencing of EGFR and RELA/P65, leading to increased apoptosis and reduced cell viability in GBM cells.
- Impaired DNA repair mechanisms, thereby enhancing cellular radiosensitivity.
- In a GBM mouse model, combined nanoparticle treatment and radiotherapy significantly prolonged survival with no observed toxicity.
Conclusions:
- Nanoparticle-mediated dual gene silencing effectively overcomes glioblastoma radioresistance.
- This strategy holds potential for improving clinical outcomes in GBM treatment.
- Presents a promising therapeutic avenue for managing this challenging brain malignancy.
