聚焦超声开放血脑屏障治疗脑胶质瘤疗效的实验研究

Opening of the blood-brain barrier through focused ultrasound in combination with drugs to treat glioma

目的采用MRI引导下聚焦超声开放脑胶质瘤大鼠血脑屏障（BBB），通过比较单次与多次给药对荷瘤鼠生存期及肿瘤大小的影响，评估多次联合给药对治疗脑胶质瘤的有效性。方法使用脑立体定位仪和微量注射泵，将C6细胞株注入50只雄性SD大鼠颅内特定区域，建立荷C6细胞株大鼠脑胶质瘤活体模型。将荷瘤大鼠随机分为5组：对照组、单次阿霉素脂质体（DOX）组、多次DOX组、单次贝伐单抗（AVS）＋DOX组、多次AVS＋DOX组。于瘤细胞种植后第12d从大鼠尾静脉分别注入SonoVue超声微泡、D0x和AVs后，采用聚焦超声开放特定区域BBB。多次组每隔48h重复一次，共3次。于治疗前、治疗后即刻、每隔1周行MRI扫描，测量各组胶质瘤大小，记录各组荷瘤鼠的生存期。结果各组（生存期范围13～90d）中位生存期分别为：对照组7d，单次DOX组12d，多次DOX组15d，单次AVS＋DOX组22d，多次AVS＋DOX组30d，各组生存期比较差异有统计学意义（P〈O．01）。各组治疗后肿瘤生长速度以单次DOX组最快，多次AVS＋DOX组最慢。随着时间延长，多次AVs＋DOX组肿瘤甚至出现缩小变化。结论MRI引导下聚焦超声开放荷脑胶质瘤大鼠BBB，促进大分子化疗药物局部释放，联合抗新生血管药并多次给药后，可明显增强化疗效果，使肿瘤生长缓慢，甚至变小，延长荷瘤鼠的生存期。

Objective To evaluate the effectiveness of treating glioma in combination with drugs multiply by comparing the size of tumor and the survival time of different groups in rat glioma after targeted bloodlbrain barrier （BBB） disruption by MRI-guided focused ultrasound. Methods The stereotaxis instruments and the 10μl gas-tight syringes were used to inject gliosarcoma cells into the targeted area of the brain in 50 male Sprague-Dawley rats. The glioma-bearing rat model was established. Each rat received either; （1） no treatment （control; n = 8） ; （2） single liposomal doxorubicin （DOX; n = 10） ; （3） multiple DOX （ n = 10） ;（4） single Avastin （AVS） and DOX （ n = 10）;（5） multiple AVS and DOX （ n = 10）. The SonoVue microbubble ultrasonic contrast agent and DOX or AVS were injected into the tail vein respectively on day 12 after implantation. The tumor size was measured by MRI on pre-treatment,immediacy and once a week of post-treatment after targeted BBB disruption by focused ultrasound,and the life span in rat glioma was recorded. Results The mediam survival of different groups in rat glioma（The range of the life span 13-90 d）：no treatment （7 d）;single DOX （12 d） ; multiple DOX （15 d）;single AVS＋ DOX （22 d）, multiple AVS ＋ DOX （30 d）. There was significant difference of the groups on mediam survival comparison （P〈 0.01 ）. The tumor growth pattern after post-treatment of different groups in rat glioma except control., single DOX was noticeable fast and multiple AVS ＋ DOX was visibly delayed comparable to other groups, and finally the tumor size of multiple AVS ＋ DOX even became small. Conclusions The microbubble blasting enhances the local tissue permeability and promotes the drug delivery of chemotherapy and anti-angiogenesis locally in glioma-bearing rats by MRI-guided focused ultrasound. Especially, the combination with drugs multiply has a synergism efficacy that may enhance the effectiveness of chemotherapy,reduce tumor growth,and even become small of the tumor size,and increase survival time significantly after BBB disruption.