Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model.
Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model.
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DOI：
10.1016/j.jconrel.2012.09.007
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发表时间：
2012-11-10
期刊：
影响因子：
--
通讯作者：
McDannold N
中科院分区：
文献类型：
--
作者：
Park EJ;Zhang YZ;Vykhodtseva N;McDannold N
曲妥珠单抗在许多转移性HER 2阳性乳腺癌患者中显示出阳性结果，但它对控制CNS中的转移不太有效，CNS仍然是复发部位。脑转移患者的不良预后被认为主要是由于血脑屏障（BBB）的存在，阻止大多数药物输送到CNS和血肿瘤屏障（BTB）的异质性和有限的渗透性。聚焦超声（FUS）脉冲群结合循环微泡可以暂时透化BBB和BTB。该技术已被研究为一种潜在的非侵入性方法，用于脑中的靶向药物递送。在这里，我们研究了在乳腺癌脑转移模型中，FUS和微泡诱导的肿瘤和周围脑组织中的BBB/BTB透化是否可以减缓肿瘤生长并提高存活率。将HER 2/neu阳性人乳腺癌细胞（BT474）接种到41只裸（nu/nu）大鼠的大脑中。治疗组中的动物在MRI引导下接受6周一次的BTB/BBB透化治疗，并联合IV给予曲妥珠单抗（2 mg/kg）。超声处理后7周，通过MRI监测肿瘤生长和存活率。从第七周开始并持续到研究结束，FUS+曲妥珠单抗组的平均肿瘤体积显著（P<0.05）小于三个对照组（无治疗、单独FUS、单独曲妥珠单抗）的平均肿瘤体积。此外，在接受FUS+曲妥珠单抗治疗的10只大鼠中，有4只大鼠的肿瘤在MRI中似乎完全消退，在3个对照组的31只大鼠中均未观察到这一结果。与未治疗组相比，曲妥珠单抗使中位生存期提高了13%，差异具有显著性（P=0.044）。与未治疗对照组相比，FUS+曲妥珠单抗治疗产生了最显著的获益（P=0.0084）。超过一半（6/10）的动物在研究终点时存活，导致中位存活时间超过83天（比未给药对照组至少长32%）。总的来说，这项工作表明，FUS和微泡诱导的BBB/BTB透化可以改善乳腺癌脑转移的结局。
Trastuzumab has shown positive results in many patients with metastatic HER2-positive breast cancer, but it is less effective for controlling metastases in the CNS, which remains a site of relapse. The poor prognosis for patients with brain metastases is thought to be largely due to the presence of the blood-brain barrier (BBB) that prevents delivery of most drugs to the CNS and to the heterogeneous and limited permeability of the blood-tumor barrier (BTB). Focused ultrasound (FUS) bursts combined with circulating microbubbles can temporarily permeabilize both the BBB and the BTB. This technique has been investigated as a potential noninvasive method for targeted drug delivery in the brain. Here, we investigated whether BBB/BTB permeabilization in the tumor and surrounding brain tissue induced by FUS and microbubbles can slow tumor growth and improve survival in a breast cancer brain metastases model. HER2/neu-positive human breast cancer cells (BT474) were inoculated in the brains of 41 nude (nu/nu) rats. Animals in the treatment group received six weekly treatments of BTB/BBB permeabilization under MRI guidance combined with IV administration of trastuzumab (2 mg/kg). Tumor growth and survival rates were monitored via MRI for seven weeks after sonication. Starting at week seven and continuing through the end of the study, the mean tumor volume of the FUS+trastuzumab group was significantly (P<0.05) less than those of the three control groups (no treatment, FUS alone, trastuzumab alone). Furthermore, in four out of 10 rats treated with FUS+trastuzumab, the tumor appeared to be completely resolved in MRI, an outcome which was not observed in any of the 31 rats in three control groups. Trastuzumab improved median survival by 13% compared to the no treatment group, a difference which was significant (P=0.044). Treatment with FUS+trastuzumab produced the most significant benefit compared to the no-treatment controls (P=0.0084). More than half (6/10) animals survived at the study endpoint, leading to a median survival time greater than 83 days (at least 32% longer than the untreated control group). Overall, this work suggests that BBB/BTB permeabilization induced by FUS and microbubbles can improve outcomes in breast cancer brain metastases.
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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：
5.7
作者：
Hynynen, K;McDannold, N;Vykhodtseva, N
通讯作者：
Vykhodtseva, N
DOI：
10.1073/pnas.0604318103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Kinoshita, Manabu;McDannold, Nathan;Hynynen, Kullervo
通讯作者：
Hynynen, Kullervo
DOI：
10.1038/nrclinonc.2011.58
发表时间：
2011-06
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.91.6.2076
发表时间：
1994-03-15
影响因子：
11.1
作者：
BOBO, RH;LASKE, DW;OLDFIELD, EH
通讯作者：
OLDFIELD, EH