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所有种类的药物都不能用于大脑，因为它们不能穿过血脑屏障。近年来，聚焦超声和微泡技术的应用已经成为一种技术，最终可以使这些药物通过血脑屏障进入大脑。然而，尽管在治疗癌症方面具有潜力，但目前的超声给药技术太不安全，而且剂量太低，无法用于治疗阿尔茨海默氏症和帕金森病等脑部疾病。我们最近的研究表明，使用传统的破坏血脑屏障的序列不能克服这些限制。在这样的序列中，一个长超声脉冲以缓慢的速率发射。每个脉冲驱动流经脉管系统的微泡，形成一系列不同的机械刺激。虽然一些刺激会产生安全的药物传递事件，但大多数刺激会产生不必要的损伤和毒性，如微血管破裂、动脉损伤和有毒的血液来源蛋白质释放到大脑中。在这个项目中，我们将利用聚焦超声中的短脉冲序列，将用于成像和治疗的小分子输送到大脑，以及通过血脑屏障的肽辅助输送方法。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，代表了克服这一挑战的有希望的方法。该项目将侧重于功能化和有针对性的过渡金属和镧系化合物的设计，最初是为核磁共振成像和光学成像技术设计的，放射化学是该项目的中期特征。聚焦超声方法将与帝国理工学院生物工程系的James Choi博士合作，香港的合作者将协助进行生物测定和钉钉肽分析，用于脑癌成像和治疗。

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.