(21c) Nanoparticle-Mediated Inhibition of DNA Repair Sensitizes Brain Tumors to Radiotherapy

Radiotherapy (RT) is an integral component of the treatment for pediatric and adult brain tumors. However, survival is frequently accompanied by one or more radiation-induced adverse developmental and psychosocial sequelae, especially in children. Therefore, strategies that enhance RT in brain tumors while sparing adjacent normal brain are expected to improve life-long outcomes. The multifunctional DNA repair protein Ape1/Ref-1 has been implicated in conferring radiation resistance in brain tumors as Ape1 activity is inversely correlated with survival in brain cancer patients. Therefore, inhibiting Ape1 specifically in brain cancer cells should greatly enhance the effects of RT. We have developed a nanoparticle (NP) delivery vehicle that can stably bind, protect, and deliver nucleic acids to brain cancer cells and tumors. Here, we used our NPs to deliver siRNA against Ape1 (siApe1). We found that NP-mediated siApe1 delivery reduced Ape1 expression and activity, which was accompanied by a greater abundance of DNA damage. This diminished the resistance of brain cancer cells to RT. Therefore, NP-mediated inhibition of Ape1 may help enhance the therapeutic effect of RT in brain tumor patients and reduce treatment-induced morbidity.