Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.
Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.
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DOI：
10.1016/j.jconrel.2018.05.005
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发表时间：
2018-07-10
期刊：
影响因子：
--
通讯作者：
Rutka JT
中科院分区：
文献类型：
--
作者：
Alli S;Figueiredo CA;Golbourn B;Sabha N;Wu MY;Bondoc A;Luck A;Coluccia D;Maslink C;Smith C;Wurdak H;Hynynen K;O'Reilly M;Rutka JT
磁共振图像引导聚焦超声（MRgFUS）已被用于实现短暂的BBB开放，而不会造成组织损伤。靶向超声波的递送引起施用的微泡与毛细血管床之间的相互作用，从而导致血管渗透性增强。在脑干中使用MRgFUS之前尚未显示，但可以在肿瘤治疗中提供价值，例如弥漫性内在脑桥胶质瘤（DIPG），其中完整的BBB有助于化疗的有限成功。我们的主要目的是确定是否可以在没有组织学损伤和功能缺陷的情况下在这个功能区使用MRgFUS。我们的第二个目标是选择一种有效的化疗药物对患者衍生的DIPG细胞系，并证明增强脑干交付时，结合MRgFUS在体内。雌性Sprague道利大鼠被随机分配到四组中的一组：1）给予微泡，但不进行MRgFUS治疗; 2）仅进行MRgFUS治疗; 3）MRgFUS +微泡;和4）MRgFUS +微泡+顺铂。通过监测心率和呼吸率进行生理评估。通过旋转棒和握力测试评估运动功能和协调性。还进行了出血（H&E）、神经元核（NeuN）和细胞凋亡（裂解的胱天蛋白酶-3）的组织学分析。在三种患者来源的DIPG细胞系（SU-DIPG IV、SU-DIPG XIII和SU-DIPG XVII）中进行了八种化疗剂的药物筛选。多柔比星被确定为有效的药剂。随后，在出现以下情况之一时，NOD/SCID/GMA（NSG）小鼠静脉注射5 mg/kg阿霉素：1）微泡，但无MRgFUS; 2）仅MRgFUS; 3）MRgFUS +微泡和4）无干预。在2小时时提取脑标本，并使用液相色谱质谱法（LC/MS）进行多柔比星定量。通过T1加权MR成像的对比增强和脑干的阳性伊文思蓝染色证实BBB开放。保持正常的心肺参数。握力和旋转棒测试表明所有组的性能均未下降。组织学分析显示没有出血、神经元丢失或细胞凋亡增加的证据。多柔比星对所有三种细胞系均表现出细胞毒性，并且已知其具有较差的BBB渗透性。在接受MRgFUS和微泡的组中，在NSG小鼠脑干中测量的最高浓度（431.5 ng/g）。这显著高于未接受干预的小鼠（7.6 ng/g）。我们的数据表明，MRgFUS用于BBB开放后，脑干的组织学和功能完整性得以保留，并且能够显著增强药物递送至该区域，从而有望治疗脑干特异性疾病。
Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient BBB opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 hours and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
11.2
作者：
McDannold N;Arvanitis CD;Vykhodtseva N;Livingstone MS
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Livingstone MS
影响因子：
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作者：
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Hawkins C
影响因子：
1.9
作者：
Ellis, Jason A.;Anderson, Richard C. E.;Ghatan, Saadi
通讯作者：
Ghatan, Saadi
影响因子：
12.7
作者：
BOTHE, HW;BODSCH, W;HOSSMANN, KA
通讯作者：
HOSSMANN, KA