Targeted multimodal stimuli-responsive nanogels for atherosclerosis imaging and therapy

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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.