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

博士项目目标：合成基于金（AuNP）或量子点（QD）技术的纳米颗粒平台，结合多种（bbb100） MRI复合物（Gd(III)），靶向血小板利用MRI研究血小板的亲和力研究血小板在动脉粥样硬化斑块形成和破裂中的作用开发预测冠状动脉疾病/中风斑块形成/破裂的工具。项目描述：心血管疾病（CVD）占全球死亡人数的31%。心血管疾病，包括心脏病发作和中风，构成了英国死亡的主要原因。CVD的机制有很多，但一个重要的步骤是血小板抑制降低，导致血小板过度活化，血小板驱动的血管炎症和闭塞性血栓的风险增加。血小板是一种血液细胞，其活化和聚集对预防血管损伤部位出血至关重要。血小板的失调可引起心血管疾病下血栓的形成。例如，在87%的中风病例中，血栓形成的基础是血管系统中存在动脉粥样硬化斑块。中风具有全球重要性，因为它占全世界所有残疾调整生命年的5%和所有死亡人数的10%。在中风中，闭塞性血栓最常见于大脑中动脉，如果不加以治疗，会导致脑损伤、严重的精神症状、瘫痪和死亡。拥有一种成像工具来了解血小板在动脉粥样硬化斑块形成和随后破裂（心脏病发作/中风的潜在原因）中的作用，将是预测高危患者的有力工具，并且能够根据CVD的分期对治疗选择进行分层。这项研究的目的是创造一系列最先进的，多聚体磁共振成像（MRI）造影剂，以血小板为目标，并在一系列动脉粥样硬化斑块模型中验证该方法。首先，将开发基于纳米颗粒（NP）的血小板特异性成像平台。这些纳米材料将基于金纳米粒子（AuNP）和InP/ZnS量子点（QDs）。它们将被一系列Gd（III）复合物功能化，以增强MRI疗效，允许通过MRI对单个细胞进行成像。纳米粒子平台将与血小板上的细胞表面受体特异性抗体功能化。接下来将是一系列体外技术来验证血小板和NP平台之间的结合。该NP平台随后将在各种斑块形成和破裂模型中进行体内研究，以确定血小板的作用和活力，作为预测心血管疾病的工具。

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.