Low-Dose Precision Radiotherapy for Glioblastoma Multiforme Via Programmed Combination for Sensitized Radioenhancement

Abstract

Although the advance in radiotherapy (RT) enables the deposition of stronger doses at tumor tissue, inadequate dose in radio-resistant glioblastoma multiforme (GBM) cells has hindered the therapeutic benefits. Herein, we demonstrated targeted sensitization-enhanced radiotherapy (TSER), a strategy that could achieve precision cell-targeted RT using linear accelerators. TSER combines a novel radio-enhancer GoldenDisk (GD), 5-aminolevulinic acid (5-ALA), low-intensity ultrasound (US), and low-dose RT showed a synergized radio-enhancement and radio-sensitization effects. Both 5-ALA and GD with its hyaluronic-acid-immobilized, gold nano-particle core-silica shell structure selectively accumulated in GBM, which synergistic-ally sensitized GBM cells to radiation under US application. Moreover, long-lasting intracellular colloidal stability of GD allows the sustainable radio-enhancement effect throughout the course of treatment. Radio-enhancement/radio-sensitization effects were confirmed by monitoring viability of healthy astrocyte to GBM cell ratio, reactive oxygen species levels, DNA damage, intrinsic apoptosis, and cell cycle arrest. Encouragingly, TSER showed a superior therapeutic effect in an orthotropic GBM model with the use of only 20% of the radiation dose than did 10-Gy RT.