Multi-functional Metal-containing Probes for Brain Imaging

血脑屏障（BBB）是英国治疗100多万神经系统疾病和脑癌患者的主要障碍。已经成功治疗其他器官疾病的整类药物不能用于大脑，因为它们不能穿过血脑屏障。近年来，聚焦超声和微泡的使用已经成为一种技术，最终可以使这些药物穿过血脑屏障进入大脑。然而，尽管它在治疗癌症方面具有潜力，但目前的超声药物输送技术太不安全，而且输送的剂量太低，对阿尔茨海默氏症和帕金森氏症等脑部疾病无效。我们最近已经表明，这些限制不能使用用于破坏BBB的常规序列来克服。在这样的序列中，以缓慢的速率发射长超声脉冲。每个脉冲驱动微泡流过脉管系统进入各种各样的机械刺激。虽然一些刺激产生安全的药物递送事件，但大多数刺激产生不希望的损伤和毒性，例如微血管破裂、动脉损伤和有毒血液衍生蛋白质释放到脑中。在这个项目中，我们将利用短脉冲序列内聚焦超声提供小分子成像和治疗的大脑，旁边的肽辅助传递方法通过BBB。分子成像方法，包括磁共振成像（MRI），正电子发射断层扫描（PET），单光子发射计算机断层扫描（SPECT）和光学成像，代表有前途的方法来克服这一挑战。该项目将专注于功能化和有针对性的过渡金属和镧系元素化合物的设计，最初设计用于MRI和光学成像技术，放射化学是该项目的中期特征。聚焦超声方法学将与帝国理工学院生物工程的James Choi博士合作进行，香港的合作者将协助进行生物测定和分析用于脑癌成像和治疗的钉合肽。

The blood-brain barrier (BBB) is the main obstacle to the development of a cure for more than a million people afflicted by neurological disorders and brain cancers in the UK. Entire classes of drugs that have successfully treated diseases in other organs cannot be used in the brain, because they cannot cross the BBB. In recent years, the use of focused ultrasound and microbubbles has emerged as a technique that could finally allow the delivery of such drugs across the BBB and into the brain.Yet despite its potential in the treatment of cancer, current ultrasound drug delivery technologies are too unsafe and deliver too low of a dose to be useful for brain diseases, such as Alzheimer's and Parkinson's disease. We have recently shown, that these limitations cannot be overcome using the conventional sequences used to disrupt the BBB. In such sequences, a long ultrasound pulse is emitted at a slow rate. Each pulse drives the microbubbles flowing through the vasculature into a diverse array of mechanical stimuli. While some of the stimuli produce safe drug delivery events, most of the stimuli produce unwanted damage and toxicity, such as microvascular rupture, arterial damage, and the release of toxic blood-derived proteins into the brain. In this project, we will utilise short pulse sequences within focussed ultrasound to deliver small molecules for imaging and therapy to the brain, alongside peptide-assisted delivery methodology through the BBB.Molecular imaging methods, including magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging, represent promising approaches to overcoming this challenge. The project will focus on the design of functionalised and targeted transition metal- and lanthanide-containing compounds, initially designed for MRI and optical imaging techniques, with radiochemistry being a medium term feature of the project. The focussed ultrasound methodology will be carried out in collaboration with Dr. James Choi in Bioengineering, Imperial College and collaborators in Hong Kong will assist with biological assays and analysis of stapled peptides for brain cancer imaging and therapy.