Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma

Glioma is the most aggressive tumor of the brain and the most efficient treatments are based on radiotherapy. However, tumors are often resistant to radiotherapy due to an enhanced DNA repair activity. Short and stabilized DNA molecules (Dbait) have recently been proposed as an efficient strategy to inhibit DNA repair in tumor. The distribution of three formulations of Dbait, (i) Dbait alone, (ii) Dbait associated with polyethylenimine, and (iii) Dbait linked with cholesterol (coDbait), was evaluated one day after intratumoral delivery in an RG2 rat glioma model. Dbait molecule distribution was assessed in the whole organ with 2D-FRI and in brain sections. CoDbait was chosen for further studies given its good retention in the brain, cellular localization, and efficacy in inducing the activation of DNA repair effectors. The radiosensitizing effect of coDbait was studied in four groups of rats bearing RG2-glioma: no treatment, radiotherapy only, coDbait alone, and CoDbait with radiotherapy. Treatment started 7 days after tumor inoculation and consisted of two series of treatment in two weeks: coDbait injection followed by a selective 6-Gy irradiation of the head. We evaluated the radiosensitizing effect using animal survival, tumor volume, cell proliferation, and vasculature characteristics with multiparametric MRI. CoDbait with radiotherapy improved the survival of rats bearing RG2-glioma by reducing tumor growth and cell proliferation without altering tumor vasculature. coDbait is therefore a promising molecular therapy to sensitize glioma to radiotherapy.