SYST-10 ENHANCING THE EFFICACY OF RADIATION THERAPY BY SURGICALLY TARGETED RADIATION-SENSITIZER LOADED FIBRIN GLUE

Abstract

Abstract Radiation therapy (RT) forms an integral part of the treatment of brain tumors. Intrinsic, relative tumor radio-resistance, normal tissue tolerance and impact on neurocognitive function, all limit the efficacy of RT. Radiation sensitizers (RS) can potentially increase efficacy on tumor cells while maintaining normal tissue toxicity. Clinical trials, employing radiation sensitizers have been done, but so far, the results have been disappointing. An important factor that could account for the low efficacy of RS in clinical trials is the blood–brain barrier (BBB). The basis for this work was the development of a RS direct delivery system (DDS), that bypasses the BBB. This is implemented by the local implantation, into the tumor resection cavity, of RS loaded slow-release fibrin glue. Localized delivery significantly increases the concentration of RS reaching the remaining infiltrative tumor cells in the brain parenchyma, while avoiding systemic side effects. Additionally, the BBB would prevent retrograde flow of the RS into the circulatory system. and the RS is protected from degradation and clearance until locally released. FG has several characteristics that make it well suited for this form of agent delivery. It has been used clinically in surgery for decades, is FDA approved, its lack of toxicity has been clearly proven, it gels rapidly and spontaneously and is easily applied. Radiation protocols utilizing two sensitizers, 5FU and Motexafin-GD, have been optimized in vitro using 3D glioma spheroid models. The results obtained in vitro have been extended to an appropriate in vivo rat brain tumor model. The goal of this project is to improve the therapeutic index of radiation therapy and is therefore clearly aimed at eventually translating to new clinical treatment protocols.