Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2020 May 29;10(1):8766. doi: 10.1038/s41598-020-65617-6.
We investigated controlled blood-brain barrier (BBB) disruption using a low-frequency clinical transcranial MRI-guided focused ultrasound (TcMRgFUS) device and evaluated enhanced delivery of irinotecan chemotherapy to the brain and a rat glioma model. Animals received three weekly sessions of FUS, FUS and 10 mg/kg irinotecan, or irinotecan alone. In each session, four volumetric sonications targeted 36 locations in one hemisphere. With feedback control based on recordings of acoustic emissions, 98% of the sonication targets (1045/1071) reached a pre-defined level of acoustic emission, while the probability of wideband emission (a signature for inertial cavitation) was than 1%. BBB disruption, evaluated by mapping the R1 relaxation rate after administration of an MRI contrast agent, was significantly higher in the sonicated hemisphere (P < 0.01). Histological evaluation found minimal tissue effects. Irinotecan concentrations in the brain were significantly higher (P < 0.001) with BBB disruption, but SN-38 was only detected in <50% of the samples and only with an excessive irinotecan dose. Irinotecan with BBB disruption did not impede tumor growth or increase survival. Overall these results demonstrate safe and controlled BBB disruption with a low-frequency clinical TcMRgFUS device. While irinotecan delivery to the brain was not neurotoxic, it did not improve outcomes in the F98 glioma model.
我们使用低频临床经颅 MRI 引导聚焦超声（TcMRgFUS）设备研究了可控的血脑屏障（BBB）破坏，并评估了伊立替康化疗药物递送至大脑的效果和在大鼠脑胶质瘤模型中的效果。动物接受了每周三次的 FUS、FUS 和 10mg/kg 伊立替康或单独伊立替康治疗。在每次治疗中，四个容积式超声波靶向一个半球中的 36 个位置。通过基于声发射记录的反馈控制，98%的声发射目标（1045/1071）达到了预先定义的声发射水平，而宽带发射的概率（惯性空化的特征）大于 1%。通过给药 MRI 对比剂后测量 R1 弛豫率来评估 BBB 破坏，发现超声波治疗半球的 BBB 破坏明显更高（P<0.01）。组织学评估发现组织影响最小。BBB 破坏后，大脑中的伊立替康浓度显著升高（P<0.001），但仅在<50%的样本中检测到 SN-38，且仅在过量的伊立替康剂量下才检测到。伊立替康与 BBB 破坏并不会阻碍肿瘤生长或增加存活率。总的来说，这些结果表明低频临床 TcMRgFUS 设备可安全且可控地破坏 BBB。尽管伊立替康递送至大脑并未引起神经毒性，但它并未改善 F98 脑胶质瘤模型的结果。
