Date28th, Mar 2019

Summary:

Researchers at Massachusetts General Hospital (MGH) headed a new study, which revealed that the uptake of therapeutic nanoparticles by glioblastomas—deadly brain tumors—could be increased...

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Researchers at Massachusetts General Hospital (MGH) headed a new study, which revealed that the uptake of therapeutic nanoparticles by glioblastomas—deadly brain tumors—could be increased through radiation therapy.

These findings raise the possibility of applying growth-factor-targeted therapy as well as immune-system-based therapy against these brain tumors.

The researchers described how the combination of pretreatment and low-dose radiation increased the delivery of nanoparticles carrying small interfering RNA (siRNA) molecules to the target tumors and considerably enhanced survival in a glioblastoma mouse model.

We found that radiation therapy primes brain tumors for enhanced uptake of nanotherapeutics, allowing us to develop a targeted nanoparticle to deliver siRNAs for both immune checkpoints and targeted therapy against the most aggressive type of brain tumor. A brief burst of radiation was able to increase uptake of the nanoparticle up to five-fold, enhancing the effects of targeted therapy, activating the immune response at the tumor site and prolonging survival.

Bakhos Tannous, PhD, Study Senior Author, Neuro-Oncology Division, Department of Neurology, Massachusetts General Hospital.

The results of the study have been reported in ACS Nano.

The EGFR growth factor—a molecule applied in targeted therapies against different forms of cancer—is expressed by around 60% of glioblastomas. However, EGFR-targeted therapies did not have a major success against the brain tumors. In a similar way, immunotherapies targeted against immune checkpoints like PD-L1 and CTLA-4 have demonstrated potential results against many different types of cancers, except for glioblastoma. A few studies have indicated a relationship between the activation of EGFR growth factor and the increased expression of PD-L1, thus raising the possibility that antitumor effects could be increased by targeting both EGFR and PD-L1.

Hence to deliver the siRNAs targeting PD-L1 and also EGFR to brain tumors, the team created a solid lipid nanoparticle, which was guided by iRGD—a tumor-targeting peptide that adheres to a molecule found on blood vessels lining the tumor, enabling it to pass through both the blood-tumor and the blood-brain barriers.

Factors like positive charge and the tiny size of this nanoparticle enable it to pass through the blood-brain barrier; and similar to other solid lipid nanoparticles, it provides an attractive option because of its biodegradability, stability, affordability, and ease of manufacture, explained the study’s first author Gulsah Erel-Akba, PhD, of MGH Neuro-Oncology and Izmir Katip Celebi University in Turkey.

To check whether the combination of pretreatment and low-dose radiation therapy would improve the therapeutic effect of the nanoparticle, the researchers compared the outcomes of four strategies in mice with gliomas.

Treatment with a nanoparticle containing a “scrambled” siRNA molecule or with radiation alone did not have any effect on either the survival of mice or tumor growth. Injection of an iRGD-guided nanoparticle carrying PD-L1/EGFR-targeting siRNAs without radiation pretreatment found to have a moderate effect on the increased survival of the mice from 21 to 24 days and tumor growth. Combination of radiation pretreatment and a siRNA-carrying nanoparticle but without an effective guiding peptide was also found to have a moderate effect on both survival and tumor growth. Radiation pretreatment along with an iRGD-guided nanoparticle carrying the PD-L1/EGFR-targeting siRNAs was found to have the greatest advantage, with survival increased to 38 days.

When the tissue collected from the tumor sites were examined, it was observed that the expression of PD-L1 was decreased and the recruitment of CD8 T cells was increased through the combined therapy, denoting an improved antitumor immune response.

According to Tannous, who is also an associate professor of Neurology at Harvard Medical School, the immunosuppressive glioblastoma microenvironment is counteracted by radiation in a number of ways, indicating a dual action of boosting nanoparticle delivery as well as improving the antitumor immune response. He noted that while factors like timing of radiation pretreatment and optimum dose are yet to be established, the same method can possibly be used for treating other kinds of aggressive tumors with siRNAs targeting varied molecular pathways.

Other co-authors of the ACS Nano paper are Litia Carvalho, PhD, Tian Tian, and Max Zinter, MGH Neuro-Oncology; Hasan Akbaba, PhD, and Ayse Gulten Kantarci, Ege University, Ismir, Turkey; Pierre Obeid, University of Balamand, Tripoli, Lebanon; E. Antonio Chiocca, MD, PhD, Brigham and Women’s Hospital; and Ralph Weissleder, MD, PhD, MGH Center for Systems Biology.

The study was supported by National Cancer Institute grant P01 CA069246, National Institute for Neurological Disease and Stroke grant P30 NS04776, and a Scientific and Technological Research Council of Turkey scholarship.

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