MR-guided Focused Ultrasound Facilitates Sonodynamic Therapy with 5-Aminolevulinic Acid in a Rat Glioma Model

Abstract

Glioblastoma multiforme (GBM) continues to have a dismal prognosis and significant efforts are being made to develop more effective treatment methods. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. It has long been known that ultrasound exposure can cause both thermal and non-thermal bioeffects and it remains an open question to what degree does temperature impact the efficacy of SDT. In order to optimize the ultrasound parameters of SDT, transcranial MRI-guided focused ultrasound (MRgFUS) and real-time MRI thermometry were used to monitor the therapy in a rat brain tumor model. Experiments were performed using a C6 intracranial glioma tumor model in 37 male Sprague Dawley rats. Treatments were performed about 7 days following tumor implantation when the tumor reached 1–3\u2009mm in diameter as determined by MRI. 5-aminolevulinic acid (5-ALA) was injected at a dose of 60\u2009mg/kg six hours before sonication. MRgFUS at 1.06\u2009MHz was delivered continuously at an in situ spatial-peak temporal-average intensity of 5.5\u2009W/cm2 for 20\u2009min. MR thermometry was acquired to monitor the temperature change in the brain during sonication. The tumor growth response for animals receiving 5-ALA alone, FUS alone, 5-ALA\u2009+\u2009FUS and a sham control group were evaluated with MRI every week following treatment. During 20\u2009min of MRgFUS at 5.5\u2009W/cm2, the temperature within the targeted brain tumor was elevated from 32.3\u2009±\u20090.5\u2009°C and 37.2\u2009±\u20090.7\u2009°C to 33.2\u2009±\u20090.9\u2009°C and 38.4\u2009±\u20091.1\u2009°C, respectively. Both the tumor growth inhibition and survival were significantly improved in the 5-ALA\u2009+\u2009FUS group with 32\u2009°C or 37\u2009°C as the starting core body (rectal) temperature. 5-ALA alone and FUS alone did not improve survival. These promising results indicate that relatively low power continuous wave transcranial MRgFUS in conjunction with 5-ALA can produce an inhibitory effect on rat brain tumor growth in the absence of thermal dose. Further investigation of the ultrasound parameters is needed to improve the therapeutic efficacy of MRgFUS and 5-ALA.