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Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque

Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (...

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Autores principales: Evans, Rhiannon J., Lavin, Begoña, Phinikaridou, Alkystis, Chooi, Kok Yean, Mohri, Zahra, Wong, Eunice, Boyle, Joseph J., Krams, Rob, Botnar, René, Long, Nicholas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332796/
https://www.ncbi.nlm.nih.gov/pubmed/32637296
http://dx.doi.org/10.7150/ntno.44712
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author Evans, Rhiannon J.
Lavin, Begoña
Phinikaridou, Alkystis
Chooi, Kok Yean
Mohri, Zahra
Wong, Eunice
Boyle, Joseph J.
Krams, Rob
Botnar, René
Long, Nicholas J.
author_facet Evans, Rhiannon J.
Lavin, Begoña
Phinikaridou, Alkystis
Chooi, Kok Yean
Mohri, Zahra
Wong, Eunice
Boyle, Joseph J.
Krams, Rob
Botnar, René
Long, Nicholas J.
author_sort Evans, Rhiannon J.
collection PubMed
description Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits(1). To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo. Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis. Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE(-/-) mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE(-/-) mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histological analysis was undertaken to confirm imaging findings through staining for macrophages, CX3CL1, elastin, tropoelastin, and iron. Results: The lead SPION agent consisted of a 10 nm iron oxide core with poly(maleicanhydride-alt-1-octadecene), (-36.21 mV, r(2) 18.806 mmol(-1)/s(-1)). The irregular faceting of the iron oxide core resulted in high relaxivity and the PMAO provided a foundation for further functionalisation on surface -COOH groups. The properties of the contrast agent, including the negative surface charge and hydrodynamic size, were designed to maximise circulation time and evade rapid clearance through the renal system or phagocytosis. In vitro testing showed that the SPION agent was non-toxic. In vivo results show that the novel contrast agent accumulates in similar vascular regions to a gadolinium-based contrast agent (Gd-ESMA) targeted to elastin, which accumulates in plaque. There was a significant difference in SPION signal between the instrumented and the contralateral non-instrumented vessels in diseased mice (p = 0.0411, student's t-test), and between the instrumented diseased vessel and control vessels (p = 0.0043, 0.0022, student's t-test). There was no significant difference between the uptake of either contrast agent between stable and vulnerable plaques (p = 0.3225, student's t-test). Histological verification was used to identify plaques, and Berlin Blue staining confirmed the presence of nanoparticle deposits within vulnerable plaques and co-localisation with macrophages. Conclusion: This work presents a new MRI contrast agent for atherosclerosis which uses an under-explored surface ligand, demonstrating promising properties for in vivo behaviour, is still in circulation 24 hours post-injection with limited liver uptake, and shows good accumulation in a murine plaque model.
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spelling pubmed-73327962020-07-06 Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque Evans, Rhiannon J. Lavin, Begoña Phinikaridou, Alkystis Chooi, Kok Yean Mohri, Zahra Wong, Eunice Boyle, Joseph J. Krams, Rob Botnar, René Long, Nicholas J. Nanotheranostics Research Paper Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits(1). To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo. Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis. Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE(-/-) mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE(-/-) mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histological analysis was undertaken to confirm imaging findings through staining for macrophages, CX3CL1, elastin, tropoelastin, and iron. Results: The lead SPION agent consisted of a 10 nm iron oxide core with poly(maleicanhydride-alt-1-octadecene), (-36.21 mV, r(2) 18.806 mmol(-1)/s(-1)). The irregular faceting of the iron oxide core resulted in high relaxivity and the PMAO provided a foundation for further functionalisation on surface -COOH groups. The properties of the contrast agent, including the negative surface charge and hydrodynamic size, were designed to maximise circulation time and evade rapid clearance through the renal system or phagocytosis. In vitro testing showed that the SPION agent was non-toxic. In vivo results show that the novel contrast agent accumulates in similar vascular regions to a gadolinium-based contrast agent (Gd-ESMA) targeted to elastin, which accumulates in plaque. There was a significant difference in SPION signal between the instrumented and the contralateral non-instrumented vessels in diseased mice (p = 0.0411, student's t-test), and between the instrumented diseased vessel and control vessels (p = 0.0043, 0.0022, student's t-test). There was no significant difference between the uptake of either contrast agent between stable and vulnerable plaques (p = 0.3225, student's t-test). Histological verification was used to identify plaques, and Berlin Blue staining confirmed the presence of nanoparticle deposits within vulnerable plaques and co-localisation with macrophages. Conclusion: This work presents a new MRI contrast agent for atherosclerosis which uses an under-explored surface ligand, demonstrating promising properties for in vivo behaviour, is still in circulation 24 hours post-injection with limited liver uptake, and shows good accumulation in a murine plaque model. Ivyspring International Publisher 2020-05-30 /pmc/articles/PMC7332796/ /pubmed/32637296 http://dx.doi.org/10.7150/ntno.44712 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Evans, Rhiannon J.
Lavin, Begoña
Phinikaridou, Alkystis
Chooi, Kok Yean
Mohri, Zahra
Wong, Eunice
Boyle, Joseph J.
Krams, Rob
Botnar, René
Long, Nicholas J.
Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title_full Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title_fullStr Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title_full_unstemmed Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title_short Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque
title_sort targeted molecular iron oxide contrast agents for imaging atherosclerotic plaque
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332796/
https://www.ncbi.nlm.nih.gov/pubmed/32637296
http://dx.doi.org/10.7150/ntno.44712
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