Local DNA repair inhibition for sustained radiosensitization in high grade gliomas

High-grade gliomas such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiation therapy (RT), and possibly surgery. Radiosensitizers that have improved the effects of RT for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated RT. Compared to previous work using locally-delivered radiosensitizers and cranial radiation, our approach - based on rational selection of agents and a clinically-relevant radiation dosing schedule - produces the strongest synergistic effects between chemo- and radio-therapy approaches to the treatment of high-grade gliomas.

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