Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Neuro Oncol. 2013 Sep;15(9):1225-35. doi: 10.1093/neuonc/not052. Epub 2013 May 2.
Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a (10)B-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that (10)B-enriched L-4-boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f.
With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. (10)B concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy.
The tumor to brain ratio of (10)B was 6.7 ± 0.5 with focused ultrasound and only 4.1 ± 0.4 in the control group (P < .01), corresponding to a mean tumor [(10)B] of 123 ± 25 ppm and 85 ± 29 ppm, respectively. (10)B uptake in infiltrating clusters treated with ultrasound was 0.86 ± 0.10 times the main tumor concentration, compared with only 0.29 ± 0.08 in controls.
Ultrasound increases the accumulation of (10)B in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma.
由于脑内相对避难所和浸润性行为，胶质母细胞瘤是一种治疗难度极大的肿瘤。治疗方法需要穿透中枢神经系统，但避免对周围组织造成损伤。硼中子俘获治疗（BNCT）是一种治疗方法，其中含硼（10）B 的药物优先积聚在恶性细胞中，并在暴露于超热中子辐照时引起高度局部损伤。研究表明，通过用渗透剂增强脑血管通透性，可以提高（10）B 富集 L-4-硼苯丙氨酸-果糖（BPA-f）复合物的摄取。我们研究了使用 MRI 引导的聚焦超声，结合可注射微泡，非侵入性和聚焦地增强 BPA-f 的摄取。
使用 Fisher 344 大鼠的 9L 胶质肉瘤肿瘤模型，使用 558 kHz 换能器和 Definity 微泡的脉冲超声破坏血脑和血肿瘤屏障，并在 2 小时内静脉内给予 BPA-f（250mg/kg）。使用成像质谱和电感耦合等离子体原子发射光谱法估计（10）B 浓度。
与对照组（4.1 ± 0.4）相比，聚焦超声治疗后的肿瘤与脑的（10）B 比值为 6.7 ± 0.5，肿瘤的平均[（10）B]为 123 ± 25ppm 和 85 ± 29ppm。与对照组相比，超声处理的浸润性团块中的（10）B 摄取量为肿瘤主要浓度的 0.86 ± 0.10 倍，而对照组仅为 0.29 ± 0.08。
超声增加了主要肿瘤和浸润细胞中（10）B 的积累。这些发现，结合聚焦超声的临床应用不断扩大，可能会提高 BNCT 和胶质母细胞瘤的治疗效果。
