Multi-functional Metal-containing Probes for Brain Imaging

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.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.