Multi-functional Metal-containing Probes for Brain Imaging

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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.