Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Sci Rep. 2019 Jul 18;9(1):10465. doi: 10.1038/s41598-019-46832-2.
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/cm 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/cm, 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.
多形性胶质母细胞瘤（GBM）的预后仍然很差，目前正在努力开发更有效的治疗方法。声动力学疗法（SDT）是一种新兴的癌症治疗方法，它结合了超声和声敏剂，以产生局部细胞毒性作用。长期以来，人们已经知道超声辐射会产生热和非热生物效应，而温度对 SDT 疗效的影响程度仍然是一个悬而未决的问题。为了优化 SDT 的超声参数，在大鼠脑肿瘤模型中使用经颅 MRI 引导的聚焦超声（MRgFUS）和实时 MRI 测温来监测治疗。实验使用 37 只雄性 Sprague Dawley 大鼠的 C6 颅内神经胶质瘤肿瘤模型进行。当肿瘤通过 MRI 确定直径为 1-3mm 时，在肿瘤植入后约 7 天进行治疗。在超声前 6 小时以 60mg/kg 的剂量注射 5-氨基酮戊酸（5-ALA）。以 1.06MHz 的频率连续传递原位空间峰值时间平均强度为 5.5W/cm 的超声 20 分钟。在超声过程中采集 MRI 测温以监测大脑中的温度变化。每周用 MRI 评估接受 5-ALA 单药、FUS 单药、5-ALA+FUS 和假对照的动物的肿瘤生长反应。在 5.5W/cm 的 20 分钟 MRgFUS 过程中，靶向脑肿瘤内的温度分别从 32.3±0.5°C 和 37.2±0.7°C 升高到 33.2±0.9°C 和 38.4±1.1°C。当起始核心体温为 32°C 或 37°C 时，5-ALA+FUS 组的肿瘤生长抑制和生存均显著改善。5-ALA 单药和 FUS 单药均不能提高生存率。这些有希望的结果表明，在没有热剂量的情况下，相对低功率连续波经颅 MRgFUS 结合 5-ALA 可以对大鼠脑肿瘤生长产生抑制作用。需要进一步研究超声参数，以提高 MRgFUS 和 5-ALA 的治疗效果。
