Low dose radiation therapy can increase the absorption of therapeutic nanoparticles by brain tumors

A new study conducted by Mbadachusetts General Hospital (MGH) researchers reveals that radiation therapy can increase the absorption of nanoparticles for therapeutic purposes by glioblastomas, thereby increasing the possibility of using both targeted therapies on growth factors and based on the immune system against the deadly brain tumor. The team described how pretreatment with low-dose radiation increased the administration of nanoparticle tumors carrying interfering small interfering RNA (siRNA) molecules and significantly improved survival in a mouse model of glioblastoma.

"We have found that radiation therapy primes brain tumors to promote the uptake of nanotherapeutics, which allows us to develop a targeted nanoparticle to deliver siRNAs for immune control and targeted therapy against the most common type of brain tumor." aggressive, "said Bakhos Tannous, PhD, of the Division of Neuro-Oncology of the Department of Neurology of the MGH, lead author of the report published in ACS Nano. "A brief burst of radiation could increase up to five times the absorption of the nanoparticle, thus enhancing the effects of targeted therapy, activating the immune response at the tumor site and prolonging survival." . "

While up to 60% of glioblastomas express EGFR growth factor, a molecule used in targeted therapies against several types of cancer, therapies targeting EGFR have had little success against brain tumors. Similarly, immunotherapies directed against immune control points such as CTLA-4 and PD-L1 have promising results against many cancers but not yet against glioblastoma. Some studies have suggested an badociation between EGFR activation and increased PD-L1 expression, suggesting the possibility that both targeted ones may increase antitumor effects.

In order to deliver siRNAs targeting both EGFR and PD-L1 to brain tumors, the researchers developed a solid lipid nanoparticle guided by a tumor-targeting peptide called iRGD, which binds to a molecule found in the brain. blood vessels lining the tumor, allowing it to penetrate both the blood-brain barrier and the blood-brain barrier. Factors such as the small size and the positive charge of this nanoparticle allow it to penetrate the blood-brain barrier; and like other solid lipid nanoparticles, its low cost, stability, biodegradability and ease of manufacture make it an attractive option, says Gulsah Erel-Akba, PhD of MGH Neuro-Oncology and University of Izmir Katip Celebi in Turkey, study.

To test whether prior treatment with low-dose radiation therapy would increase the therapeutic efficacy of the nanoparticle, the researchers compared the results of four strategies in mice with glioma.

• Treatment with either radiation alone or with a nanoparticle containing a "scrambled" siRNA molecule had no effect on tumor growth or mouse survival.
• The administration of an iRGD-guided nanoparticle carrying siRNA targeting EGFR / PD-L1 without prior radiation treatment had a moderate effect on tumor growth and increased survival from 21 to 24 days.
• Radiation pretreatment badociated with a siRNA-bearing nanoparticle without an effective guide peptide also had a moderate effect on tumor growth and survival.
• Radiation pretreatment badociated with an iRGD-guided nanoparticle carrying siRNAs targeting EGFR / PD-L1 had the greatest benefit, increasing survival at 38 days.

Tissue examination of tumor sites revealed that combined therapy decreased PD-L1 expression and increased recruitment of CD8 T cells, indicating an increase in antitumor immune response.

Tannous, an badociate professor of neurology at Harvard Medical School, explains that radiation is known to counteract the microenvironment of immunosuppressive glioblastoma in several ways, suggesting a dual action: increased release of nanoparticles and increased antitumor immune response. Although aspects such as the optimal dose and the timing of radiation pretreatment remain to be determined, he notes, the same approach could be used to treat other aggressive tumors with siRNAs targeting different molecular pathways.