Targeted multimodal stimuli-responsive nanogels for atherosclerosis imaging and therapy

PHD项目的目的：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、刺激响应的纳米凝胶将响应斑块中存在的酶改变其结构，并在时空监测的同时向动脉粥样硬化斑块输送治疗和成像药物。心血管疾病(CVD)是全球主要的死亡原因。仅在欧盟，心血管疾病造成的医疗费用每年就高达近2000亿欧元。生活方式、高胆固醇饮食(称为西式饮食)的消费以及人口老龄化导致了心血管疾病病例的增加。心血管疾病的主要原因是动脉粥样硬化，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之后，其大小会增大，这可能会导致它们变得不稳定，从而导致破裂。随之而来的血栓形成可能会导致堵塞，最终导致心脏病发作或缺血性中风。目前，还没有可用的成像方法来检测不稳定的动脉粥样硬化斑块的生物学活性。因此，有必要开发改进的成像技术，允许对动脉粥样硬化进行成像和治疗。该项目将开发纳米凝胶形式的靶向纳米药物，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。这种治疗性蛋白将被选为一种有效的炎症解除剂，已被证明对动脉粥样硬化治疗有效。这种纳米凝胶结构将包含一种基于Gd的造影剂，使斑块内的纳米凝胶能够通过磁共振成像进行可视化。纳米凝胶是纳米尺寸的纳米颗粒，能够保留大量的水或生物流体，从而保持其结构。这种非常有利和独特的性质使其成为输送生物药物(如酶和基于Gd的造影剂)的理想纳米平台，这两种药物的成分都从水环境中受益。纳米凝胶具有极其有用的特性，因为它们提供：1)生物敏感有效载荷的包封性稳定性，2)它们具有低免疫原性和毒性，并且可以被设计为完全可生物降解，3)可以在一个纳米凝胶中传递多种生物或成像有效载荷，便于将治疗与成像相结合，4)它们的合成可以是水基的，很容易缩放，5)它们是软纳米颗粒，可以很容易地在血流动力学下挤过受限的部位。该项目的理想候选者将拥有化学或生物相关领域的学位，如果他们有一些合成经验的话。申请者应具有良好的学术记录，对临床前成像感兴趣，优秀的沟通技能，并能够在协作的跨学科环境中工作。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分析。学生还将接受使用核磁共振技术对动脉粥样硬化进行分子成像的培训，与动物一起工作，并进行体外组织分析。

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.