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

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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 plateletsInvestigate affinity for platelets using MRIInvestigate platelet role in atherosclerosis plaque formation and ruptureDevelop 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.