PDF(Pubmed)
Abstract：
Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound. Methods: Microbubbles functionalised with anti-VCAM1 were synthesised and shown to bind to VCAM-1-expressing cells in vitro. Experiments were then conducted in vivo in a unilateral breast cancer brain metastasis mouse model using Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening. Following injection of Gd-DTPA and targeted microbubbles, the whole brain volume was simultaneously exposed to ultrasound (0.5 MHz, 10% duty cycle, 0.7 MPa peak negative pressure, 2 min treatment time). T1-weighted MRI was then performed to identify BBB opening, followed by histological confirmation via immunoglobulin G (IgG) immunohistochemistry. Results: In mice treated with targeted microbubbles and ultrasound, statistically significantly greater extravasation of Gd-DTPA and IgG was observed in the left tumour-bearing hemisphere compared to the right hemisphere 5 min after treatment. No acute adverse effects were observed. There was no investigation of longer term bioeffects owing to the nature of the study. Conclusion: The results demonstrate the feasibility of using targeted microbubbles in combination with low intensity ultrasound to localise opening of the BBB to metastatic sites in the brain. This approach has potential application in the treatment of metastatic tumours whose location cannot be established a priori with conventional imaging methods.
摘要：
大脑中的转移性肿瘤现在是癌症死亡的主要原因之一。由于晚期诊断和治疗穿过血脑屏障(BBB)的不良递送的组合,目前的治疗在很大程度上是无效的。磁共振成像（MRI）造影剂与VCAM-1（抗VCAM1）的单克隆抗体偶联已被证明能够检测微转移，体积比目前临床上可检测到的体积小两到三个数量级。这项研究的目的是利用这种靶向方法，使用功能化的微泡和超声在早期转移部位实现局部和暂时的BBB开放。方法:合成用抗VCAM1功能化的微泡,并显示在体外与表达VCAM-1的细胞结合。然后使用钆-DTPA(Gd-DTPA)增强的MRI在单侧乳腺癌脑转移小鼠模型中进行体内实验以检测BBB开放。注射Gd-DTPA和靶向微泡后，整个大脑体积同时暴露于超声波(0.5兆赫，10%占空比,0.7MPa峰值负压,2min处理时间)。然后进行T1加权MRI以识别BBB开口，然后通过免疫球蛋白G（IgG）免疫组织化学进行组织学确认。结果：在用靶向微泡和超声治疗的小鼠中，与治疗后5分钟的右半球相比，在左侧荷瘤半球观察到Gd-DTPA和IgG的外渗在统计学上显着增加。没有观察到急性不良反应。由于研究的性质，没有对长期生物效应进行研究。结论：结果证明了使用靶向微泡与低强度超声组合以将BBB的开放定位到大脑中的转移部位的可行性。这种方法在转移性肿瘤的治疗中具有潜在的应用，其位置无法通过常规成像方法先验确定。
