Synthesis of multimeric nanoparticle-based MRI agents for detecting the role of platelets in Atherosclerosis

Aim of the PhD Project:

Synthesise nanoparticle platforms based on gold (AuNP) or quantum dot (QD) technologies with multiple (>100) MRI complexes (Gd(III)), targeted to platelets
Investigate affinity for platelets using MRI
Investigate platelet role in atherosclerosis plaque formation and rupture
Develop a tool for predicting plaque formation/rupture in coronary artery disease/stroke.

Project Description:

Cardiovascular disease (CVD) is responsible for 31% of worldwide deaths. CVD, including heart attacks and strokes, constitutes the leading cause of mortality in the UK. The mechanisms underlying CVD are numerous, but a significant step is a decrease in platelet inhibition, leading to platelet hyperactivation, platelet-driven vascular inflammation and an elevated risk of occlusive thrombi. Platelets are blood cells whose activation and aggregation are crucial for the prevention of bleeding at the sites of vascular injury. Deregulation in the platelet can cause the formation of thrombi under CVD. For instance, underlying the thrombus formation in 87% of stroke cases is the presence of atherosclerotic plaques in the vasculature. Stroke is of global importance as it is responsible for 5% of all disability-adjusted life-years and 10% of all deaths worldwide. Within stroke the occlusive thrombi are most commonly present in the middle cerebral artery which, if not treated, leads to brain damage, profound mental symptoms, paralysis, and death. Having an imaging tool to understand the role of the platelet in atherosclerotic plaque formation and subsequent rupture (the underlying cause of heart attacks/stroke), would represent a powerful tool in predicting at-risk patients, and the ability to stratify therapeutic choices depending on the stage of CVD.

The aim of this studentship is to create a series of state-of-the-art, multimeric magnetic resonance imaging (MRI) contrast agents that target the platelets and validate the approach in vivo in a series of atherosclerotic plaque models. Firstly, a platelet-specific platform based on nanoparticles (NP) for imaging will be developed. These nanomaterials will be based on gold nanoparticles (AuNP) and InP/ZnS quantum dots (QDs). They will be functionalised with a series of Gd(III) complexes to enhance MRI efficacy, allowing the imaging of single cells via MRI. The nanoparticle platform will be functionalised with antibodies specific for cell surface receptors on the platelet. This will be followed by a range of in-vitro techniques to validate binding between the platelet and the NP platform.

This NP platform will then be studied in vivo in a variety of plaque formation and rupture models to identify the platelet role and viability as a tool to predict CVD.

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.