使用脉冲聚焦超声联合微泡造影剂打开血脑屏障并提高替莫唑胺治疗脑胶质母细胞瘤的疗效。
Opening the Blood-Brain Barrier and Improving the Efficacy of Temozolomide Treatments of Glioblastoma Using Pulsed, Focused Ultrasound with a Microbubble Contrast Agent.
机构信息
Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Ultrasonography, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
出版信息
Biomed Res Int. 2018 Nov 11;2018:6501508. doi: 10.1155/2018/6501508. eCollection 2018.
OBJECTIVE
To explore the effects of pulsed, focused, and microbubble contrast agent-enhanced ultrasonography (mCEUS) on blood-brain barrier (BBB) permeability and the efficacy temozolomide for glioblastoma.
METHODS
Wistar rats (n = 30) were divided into three groups (n = 10 per group) to determine optimal CUES conditions for achieving BBB permeability, as assessed by ultrastructure transmission electron microscopy (TEM) and western blot assays for the tight junction protein claudin-5. Optimized mCEUS effects on BBB permeability were subsequently confirmed with Evans blue staining (2 groups of 10 rats). The glioma cell line 9L was injected into the brain striatum of Wistar rats. After temozolomide chemotherapy, we detected glial fibrillary acidic protein (GFAP) levels in serum by enzyme-linked immunosorbent assay (ELISA) and in brain tissue by western blot, immunocytochemistry, and real-time quantitative polymerase chain reaction (qPCR).
RESULTS
BBB permeability was maximized with 1 ml/kg contrast agent mCEUS delivered via 10-min intermittent launches with a 400-ms interval. Evans blue staining confirmed BBB permeability following ultrasonic cavitation in the control group (P < 0.05). Following temozolomide chemotherapy, levels of the tumor marker GFAP were increased in the group with ultrasonic cavitation compared with the control group (P < 0.05).
CONCLUSIONS
When rats were treated by mCEUS with intermittent launches (interval, 400 ms) and injected with 1 mg/kg contrast agent, BBB permeability was increased and temozolomide BBB penetration was enhanced, therapeutic enhancement for glioblastoma.
目的
探讨脉冲、聚焦和微泡对比剂增强超声（mCEUS）对血脑屏障（BBB）通透性的影响，以及替莫唑胺治疗胶质母细胞瘤的疗效。
方法
将 Wistar 大鼠（n=30）分为三组（每组 n=10），通过超微结构透射电镜（TEM）和紧密连接蛋白 Claudin-5 的 Western blot 检测评估 BBB 通透性，以确定最佳 CUES 条件。随后，通过 Evans 蓝染色（两组各 10 只大鼠）验证 mCEUS 对 BBB 通透性的优化效果。将 9L 神经胶质瘤细胞系注射到 Wistar 大鼠脑纹状体。在替莫唑胺化疗后，通过酶联免疫吸附试验（ELISA）检测血清中神经胶质纤维酸性蛋白（GFAP）水平，通过 Western blot、免疫细胞化学和实时定量聚合酶链反应（qPCR）检测脑组织中 GFAP 水平。
结果
采用 1ml/kg 对比剂的 mCEUS，通过 10 分钟的间歇发射，间隔 400ms，可使 BBB 通透性最大化。Evans 蓝染色证实了对照组超声空化后的 BBB 通透性（P<0.05）。替莫唑胺化疗后，与对照组相比，超声空化组肿瘤标志物 GFAP 水平升高（P<0.05）。
结论
当大鼠接受间歇发射（间隔 400ms）的 mCEUS 治疗，并注射 1mg/kg 对比剂时，BBB 通透性增加，替莫唑胺穿透 BBB 增强，从而增强胶质母细胞瘤的治疗效果。
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