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

PHD项目的目标：合成以金(AuNP)或量子点(QD)技术为基础的纳米颗粒平台和多个(&gt；100)MRI络合物(Gd(III))，目标是血小板使用磁共振成像研究血小板对血小板的亲和力调查血小板在动脉粥样硬化斑块形成和破裂中的作用开发一种工具，用于预测冠状动脉疾病/中风的斑块形成/破裂。项目描述：心血管疾病(CVD)是全球31%的死亡原因。心血管疾病，包括心脏病发作和中风，是英国人死亡的主要原因。CVD的机制很多，但重要的一步是减少对血小板的抑制，导致血小板过度激活、血小板驱动的血管炎症和闭塞性血栓的风险增加。血小板是一种血细胞，其活化和聚集对于防止血管损伤部位的出血至关重要。在心血管疾病中，血小板调节失调会导致血栓的形成。例如，在87%的中风病例中，血栓形成的基础是血管系统中动脉粥样硬化斑块的存在。中风具有全球重要性，因为它造成了全世界5%的残疾调整生命年和10%的死亡。在中风中，闭塞血栓最常出现在大脑中动脉，如果不治疗，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/中风的根本原因)中的作用，将是预测高危患者的强大工具，并能够根据CVD的阶段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，以血小板为靶点，并在体内一系列动脉粥样硬化斑块模型中验证该方法。首先，将开发一种基于纳米粒子(NP)的血小板特异性成像平台。这些纳米材料将以金纳米粒子(AuNP)和InP/ZnS量子点(Qds)为基础。它们将被一系列Gd(III)络合物功能化，以增强MRI效果，允许通过MRI对单细胞进行成像。纳米颗粒平台将使用针对血小板上细胞表面受体的抗体进行功能化。随后将采用一系列体外技术来验证血小板和NP平台之间的结合。然后，将在体内通过各种斑块形成和破裂模型研究NP平台，以确定作为预测心血管疾病的工具的血小板的作用和生存能力。

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.