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

Sheng-Kai Wu,Stuart L Marcus,Marc A Santos,Kullervo Hynynen

doi:10.1038/s41598-019-46832-2

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 mm in diameter as determined by MRI. 5-aminolevulinic acid (5-ALA) was injected at a dose of 60 mg/kg six hours before sonication. MRgFUS at 1.06 MHz was delivered continuously at an in situ spatial-peak temporal-average intensity of 5.5 W/cm2 for 20 min. 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 + FUS and a sham control group were evaluated with MRI every week following treatment. During 20 min of MRgFUS at 5.5 W/cm2, the temperature within the targeted brain tumor was elevated from 32.3 ± 0.5 °C and 37.2 ± 0.7 °C to 33.2 ± 0.9 °C and 38.4 ± 1.1 °C, respectively. Both the tumor growth inhibition and survival were significantly improved in the 5-ALA + FUS group with 32 °C or 37 °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.

Highlights

Photodynamic therapy (PDT) is one promising approach to treat tumors under certain conditions
An ISPTA of 5.5 W/cm[2] was selected for the treatment efficacy experiments because under this exposure condition, the brain temperature was elevated by approximately 2 °C which was found to be suitable for the experimental design of this study
We have demonstrated that an sonodynamic therapy (SDT) regimen of 5-aminolevulinic acid (5-ALA) combined with magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) (MRgFUS) at 5.5 W/cm[2] (ISPTA) for 20 min can significantly inhibit tumor growth and prolong survival in an intracranial rat glioma tumor model in the absence of thermal dose

Summary

Introduction

Photodynamic therapy (PDT) is one promising approach to treat tumors under certain conditions. PDT is not effective for the treatment of deep-seated tumors due to the poor penetration depth of light[4]. More recently it was shown that some photosensitizers can be used as sonosensitizers to absorb energy from ultrasound in order to potentiate tumor cell death in animal models, a so-called sonodynamic therapy (SDT)[7,8]. The significant advantage of SDT over PDT is that ultrasound can be well-focused and penetrate deep into the target tissue[9]. MR thermometry was used to monitor the temperature change during the treatment at two resting core body temperatures, namely 32 °C and 37 °C These were chosen to investigate the effect of absolute temperature elevation as measured during the SDT sonication on the resulting tumor control capability and to compare the results with previous literature[15].

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Results

Conclusion