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Nanoparticles for Molecular Imaging of Atherosclerosis: from Diagnosis to Treatment

Periodic Reporting for period 1 - NanoMATe (Nanoparticles for Molecular Imaging of Atherosclerosis: from Diagnosis to Treatment)

Reporting period: 2015-09-01 to 2017-08-31

Atherosclerosis is the formation of plaques (atheromas) in the medium and large arteries. The related occlusion may disrupt the blood flow to target organs, leading to heart disease and stroke - the most common causes of death in developed countries. The identification of the blockage is mainly due to the emerging of symptoms and to cardiovascular imaging that is traditionally focused on the anatomy of the atherosclerotic plaque. Unfortunately the degree of vessel narrowing caused is not the only feature able to predict the clinical outcome. In fact the molecular composition of the atheroma represent the most important indicator of future plaque destabilization and complications. Immune response plays a crucial role from the onset of the pathology through its progression, up to clinical manifestations. Consequently researchers worldwide are developing innovative approaches for molecular imaging of inflammation in atherosclerosis as new diagnostic tools. Various imaging technologies have been developed; however, each approach presents severe weaknesses. In the last decade, surface enhancement Raman spectroscopy (SERS) is developing as an effective molecular imaging optical modality in biomedicine because it offers many advantages over traditional technologies, including better sensitivity, and a superior multiplexing capability. Therefore, the primary aim of the proposal has been the development of a highly-sensitive and selective but relatively affordable SERS-based system to measure inflammation in atherosclerotic vessels.
We have been able to successfully develop a SERS-NP based system for multiplexing detection of biomarkers of vascular inflammation in vitro, ex vivo in human atherosclerotic plaques, and in vivo in humanised murine models.
To the best of our knowledge, this is the first demonstration of SERS multiplex targeted imaging of vascular inflammation. The further development of our platform (see figure) and translation into the clinical setting would benefit patients by improving their health and the community at large as the cost of current atherosclerosis-related treatments and morbidity are significant.

Figure Legend:
A prospective rational for SERS based-diagnostics for atherosclerotic inflammation. A) The identification of inflammatory biomarkers in atherosclerotic plaques may be achieved via the intravenous injection of SERS-detectible bio-functionalised nanoparticles into a patient. Such nanoparticles would consist of; a noble metal core for surface enhancement of Raman spectra; a Raman reporter to provide a pre-determined Raman signature; a polymer coating (such as Polyethylene glycol, PEG) to reduce nanoparticle interaction with the immune system and prolong blood circulation time; a targeting molecule such as an antibody or aptamer to confer molecular specificity. These nanoparticles would circulate in the vasculature, binding to inflammatory biomarkers such as adhesion molecules, macrophage, T and B cell activation markers, and potentially atherosclerosis associated biomarkers. Following binding these nanoparticles would then be detectable at significant tissue depths, for example within the carotid artery, via surface-enhanced spatially offset Raman spectroscopy (SESORS). B) Following the injection of bio-functionalised nanoparticles and the investigation of atheroprone regions of the vasculature with SESORS, detection of biomarker specific bio-functionalised nanoparticles would be recorded. Consequently this would provide clinicians with a technology capable of detecting a panel of biomarkers suitable for subsequent correlation with disease severity and implementation as a potential predictor of disease outcome. A hypothetical example is provided whereby the detection of bio-functionalised nanoparticles indicated the presence of biomarkers A, D and E, and the absence of biomarkers B and C following SESORS investigation of a carotid artery. Reprinted from MacRitchie et al. Molecular imaging of atherosclerosis: spotlight on Raman spectroscopy and surface-enhanced Raman scattering. Heart. 2017. pii: heartjnl-2017-311447, distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license.
A prospective rational for SERS based-diagnostics for atherosclerotic inflammation