Targeted multimodal stimuli-responsive nanogels for atherosclerosis imaging and therapy

博士项目目标：该项目旨在开发能够靶向、成像和治疗动脉粥样硬化斑块的新型纳米凝胶。这些智能的、对刺激有反应的纳米凝胶将根据斑块中存在的酶改变其结构，并在以时空方式监测的同时向动脉粥样硬化斑块输送治疗和显像剂。心血管疾病（CVD）是世界范围内死亡的主要原因。仅在欧盟，心血管疾病每年造成的医疗费用就高达近2000亿欧元。生活方式、高胆固醇饮食（称为西方饮食）的消费以及人口老龄化导致心血管疾病病例的增加。心血管疾病的主要病因是动脉粥样硬化，这是一种由炎症引起的动脉慢性疾病。动脉粥样硬化斑块的形成伴随着其大小的增长，这可能导致它们变得不稳定，导致破裂。随后形成的血栓会导致血管堵塞，最终导致心脏病发作或缺血性中风。目前，尚无基于斑块生物活性来检测不稳定动脉粥样硬化斑块的影像学方法。因此，有必要发展改进的成像技术，使动脉粥样硬化的成像和治疗都能实现。该项目将以纳米凝胶的形式开发靶向纳米药物，以成像动脉粥样硬化斑块，并通过斑块中存在的酶的作用释放治疗性蛋白质。治疗性蛋白将被选择为一种有效的炎症解决剂，已证实对动脉粥样硬化治疗有效。纳米凝胶结构将包含一种基于钆的造影剂，允许纳米凝胶在斑块内的传递通过MRI可视化。纳米凝胶是纳米大小的纳米颗粒，具有保留大量水或生物流体的能力，从而保持其结构。这种非常有利和独特的特性使它们成为递送生物药物（如酶和基于gd的造影剂）的理想纳米平台，这两种成分都受益于水环境。纳米凝胶具有非常有用的特性，因为它们提供：1)生物敏感有效载荷的包封稳定性，2)它们具有低免疫原性和毒性，并且可以被设计成完全可生物降解的，3)多个生物或成像有效载荷可以在单个纳米凝胶中递送，促进治疗与成像的结合，4)它们的合成可以是水基的，容易伸缩，5)它们是柔软的纳米颗粒，可以在血流动力学纯流动下容易挤压通过受限部位。该项目的理想人选应具有化学或生物相关领域的学位，前提是他们有一些合成经验。申请人应具有良好的学术成绩，对临床前影像学感兴趣，优秀的沟通能力，能够在协作，跨学科的环境中工作。学生将接受组织培养方面的培训，以便能够处理细胞并进行细胞毒性试验。学生还将接受使用MRI技术进行动脉粥样硬化分子成像的培训，与动物一起工作，并进行离体组织分析。

Aim of the PhD Project:This project aims to develop novel nanogels capable of targeting, imaging and treating atherosclerotic plaques.These smart, stimuli-responsive nanogels will change their structure in response to enzymes present in the plaques and deliver both therapeutic and imaging agents to atherosclerotic plaques while being monitored in a spatiotemporal manner.Cardiovascular disease (CVD) is the leading cause of death worldwide. Healthcare costs as a result of CVD amount to almost EUR 200 billion a year in the European Union alone. Lifestyle, consumption of high-cholesterol diets (known as the Western-type diet), and an ageing population have led to an increase in CVD cases. The major cause of CVD is atherosclerosis, an inflammation driven chronic disease of the arteries. The creation of atherosclerotic plaques is followed by a growth in their size, which can cause them to become unstable, leading to rupture. The ensuing thrombosis can cause blockages and ultimately lead to a heart attack or ischaemic stroke. Currently, there are no available imaging methods to detect unstable atherosclerotic plaques based on the biological activity of the plaque. Thus, there is a need to develop improved imaging technologies that allow both imaging and treatment of atherosclerosis.This project will develop targeted nanomedicines in the form of nanogels to image atherosclerotic plaques and release a therapeutic protein through the action of enzymes present in the plaque. The therapeutic protein will be chosen to be a potent resolver of inflammation with proven efficacy for atherosclerosis therapy. The nanogel structure will contain a gadolinium-based contrast agent, allowing the delivery of the nanogels within the plaque to be visualised by MRI.Nanogels are nanometre-sized nanoparticles that have the ability to retain high volumes of water or biological fluids, and hence maintain their structure. This highly advantageous and unique property makes them an ideal nanoplatform for the delivery of biological drugs such as enzymes and also Gd-based contrast agents, both components of which benefit from an aqueous environment. Nanogels have extremely useful properties as they offer: 1) encapsulation stability for biologically-sensitive payloads, 2) they have low immunogenicity and toxicity, and can be designed to be fully biodegradable, 3) multiple biological or imaging payloads can be delivered in a single nanogel, facilitating the combination of therapies with imaging, 4) their synthesis can be water-based and easily scaled, and 5) they are soft nanoparticles that can easily squeeze through restricted sites under haemodynamic sheer flow.The ideal candidate for the project would have a degree in chemistry or in a biology-related field, provided they have some experience of synthesis. The applicant should have a strong academic record, an interest in preclinical imaging, excellent communication skills and be able to work in a collaborative, interdisciplinary environment. The student will be trained in tissue culture so as to be able to handle cells and perform cytotoxicity assays. The student will also receive training in molecular imaging of atherosclerosis using MRI techniques, work with animals, and perform ex vivo tissue analysis.