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Imaging Chemistry and Biology (pre-2019)

Developing new targeted molecular contrast agents for imaging inflammation of vulnerable plaques

Project ID: 2015_204

Student: Rhiannon Evans

1st supervisor: Rob Krams
2nd supervisor: Rene Botnar, King’s College London
3rd supervisor: Nick Long, Imperial College London

This project is multi-faceted so it would suit students with strengths in either physics/bioengineering or chemistry. We seek the best candidate who wants to carry out some synthetic chemistry, alongside the bioengineering and image analysis.

Coronary heart disease (CHD) is the global leading cause of death. In the UK, acute coronary syndromes (ACS) cause ~60% of CHD deaths and lead to ~240,000 hospitalisations each year, incurring direct healthcare costs of ~£1.7 billion annually. The majority of the mortality of CHD is related to the rupture of a thin cap fibro-atheroma (TCFA). The characteristics of a rupture-prone plaque are that of a large and soft lipid-rich necrotic core covered by a thin and inflamed fibrous cap. Associated features include large plaque burden, expansive remodelling preventing luminal obstruction (mild stenosis by angiography), neo-vascularization, plaque hemorrhage, adventitial inflammation, and a “spotty” pattern of calcifications. Despite considerable world-wide efforts, specific diagnostic tools for detection of vulnerable plaques are currently lacking .

Molecular imaging enables detection beyond (vascular) anatomy and is of special interest for detection of plaque vulnerability, as structural changes are considered relatively stable (weeks to months), as compared to the kinetics of macrophage uptake (hours to days). The dynamic accumulation of activated macrophages, associates with plaque vulnerability through release of activated MMPs. Site-specific accumulation and concentration of macrophages occur through surface receptors expressed on the endothelium. This process may lead to high local activation of MMPs, local weak spots in the extra-cellular matrix and when these spots coincide with high peaks in mechanical stress, rupture may occur.

Several contrast agents have been proposed to target proteins and cell surface receptors of interest, including targeted micelles, liposomes, superparamagnetic iron oxide particles (SPIOs) and gold/silica particles. Nanotechnology e.g. the design of nanoparticles (1-100 nm), is emerging as a new area within the field of molecular imaging, partially through superior properties over other contrast material, including high payloads, high contrast, high retention and short washout kinetics from plaques, efficient coupling to proteins and antibodies and custom-made composition. This latter property enables design of probes for MRI, CT and OCT (optical coherence tomography), the main imaging modalities for cardiovascular diagnosis. In this project, the new nanoparticle materials will be synthesised (ICL-Chem) and imaged with microscopic systems available in Imperial College (ICL-BioEng) and subsequently, with MRI/PET/CT in murine models and a novel atherosclerotic pig model (KCL-Imag).

The Long group have expertise in the design and synthesis of a range of nanoparticulate contrast materials – ranging from functionalised iron and manganese oxide nanoparticles (Fig. 1), to gold- and silica-containing materials (refs: 1, 2). The Krams group has long-lasting experience in quantitative imaging of vulnerable plaques in animal models, in the isolation and imaging of isolated macrophages, and in the generation of novel antibodies (refs: 3, 4). The Botnar group has experience with the development of cardiovascular MRI sequences and validation of novel contrast agents for preclinical and clinical molecular imaging of atherosclerosis (Fig. 2) (refs: 5, 6).

Figure 1:  Tumour-uptake of MRI-active functionalised MnO nanoparticles.

Figure 2: Imaging of coronary thrombus using motion compensated inversion recovery MRI.

The collaboration of these groups enables evaluation of the hypothesis that “molecular imaging offers a new and unique method to identify progress and rupture-risk of vulnerable plaques”. It is expected that by adding extra functionality to standard imaging, molecular imaging will improve precision/stratification of diagnosis and aid therapy.

References:
1.   J. Gallo, N. J. Long et al, J. Mat. Chem. B, 2014, 2, 868-876.
2.   J. Gallo, N. J. Long et al, Angew. Chem. Int. Ed., 2014, 53, 9550-9554.
3.   J. Frueh et.al. Cardiovascular Research, JUL 2013.
4.   R. Pedrigi et al, Arteriosclerosis Thrombosis and Vascular Biology, 2014, 223-245.
5.   A. Phinikaridou et al, Molecules, 2013, 18(11), 14042-69.
6.   M. Makowski et al, Circulation, 2013, 128(11), 1244-55

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