1st Supervisor: James Wilton-Ely, Imperial College London
2nd Supervisor: Alkystis Phinikaridou, King’s College London
Additional Supervisors: Nazila Kamaly, Imperial College London; René Botnar, King’s College London
Clinical Champion: Ramzi Khamis, Imperial College London
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.
Project Description / Background:
Cardiovascular disease (CVD) is the leading cause of death worldwide . Healthcare costs as a result of CVD amount to almost €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 . In the body, cholesterol is transported in plasma by apolipoprotein particles. When these cholesterol-apolipoprotein particles, including low-density lipoproteins (LDL) accumulate in the sub-endothelium of arteries in regions of disturbed blood flow, they are retained and become oxidised, leading to an accumulation of oxidised low-density lipoproteins (oxLDL). Eventually, atherosclerotic plaques grow in size and may become unstable, leading to rupture or endothelial erosion with ensuing thrombosis, causing vessel occlusion and myocardial infarction 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 [3,4] in the form of nanogels to image atherosclerotic plaques and release a therapeutic protein through the action of plaque enzymes including matrix metalloproteinases (MMP-2). The therapeutic protein will be Annexin A1, 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. Along with the Annexin A1 cargo, the nanogel will also contain the fluorophore, calcein, allowing the delivery of the nanogel contents to be followed by optical imaging.
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 [3,4]. Nanogels have superior 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. Nanogels can also be functionalised with targeting units, such as tropoelastin [6,7].
The ideal candidate would have a degree in chemistry or in a biology-related field, provided they have 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.
Figure 1: Illustration of targeted atherosclerosis treatment using enzymatic action to release imaging and therapeutic contents of nanogel with images showing resulting MRI contrast enhancement and fluorescence response
- Heart disease and stroke statistics – 2017 update: A report from the American Heart Association. Benjamin et al., Circulation 2017 (doi.org/10.1161/CIR.0000000000000485).
- (Re)solving atherosclerosis. Soehnlein, Sci. Transl. Med. 2015 (doi.org/10.1126/scitranslmed.aaa5355).
- Targeted interleukin-10 nanotherapeutics developed with a microfluidic chip enhance resolution of inflammation in advanced atherosclerosis. Kamaly et al, ACS Nano 2016 (doi.org/10.1021/acsnano.6b01114).
- Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Kamaly et al Sci. Transl. Med. 2015 (doi.org/10.1126/scitranslmed.aaa1065).
- Polyfunctionalised nanoparticles bearing robust gadolinium surface units for high relaxivity performance in MRI. Wilton-Ely et al, Chem. Eur. J., 2019 (doi.org/10.1002/chem.201901820), 2020 (doi.org/10.1002/chem.201904757)
- Tropoelastin: A novel marker for plaque progression and instability. Phinikaridou, Botnar et al, Circ. Cardiovasc. Imaging, 2018 (doi.org/10.1161/CIRCIMAGING.117.007303).
- Tropoelastin: An in vivo imaging marker of dysfunctional matrix turnover during abdominal aortic dilation. Botnar, Phinikaridou et al, Cardiovascular Research, 2019 (doi.org/10.1093/cvr/cvz178)