Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque

Abstract

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...

A Critical Review of the Use of Surfactant-Coated Nanoparticles in Nanomedicine and Food Nanotechnology

“…The T1 relaxation time of hydrogen ions is observed to be greatly shortened by the presence of surrounding transition elements (Cr 2+ , Cr 3+ , Mn 2+ , Mn 3+ , Fe 2+ , and Fe 3+ ) and lanthanides (Gd 3+ and Dy 3+ ), and MRI contrast agent containing nanoparticles composed of these elements have been studied ( Figure 2B ). 238 , 239 For example, ferucarbotran (Resovist ® , Bayer Healthcare, Leverkusen, Germany), ferumoxides (Feridex ® , Bayer Healthcare, Leverkusen, Germany), erumoxtran-10 (Combidex ® , AMAG Pharma, Waltham, MA), and NC100150 (Clariscan ® , Nycomed, Zürich, Switzerland), which are composed of SPION, have been used in clinical practice as MRI contrast agent nanoparticles. 240 On the other hand, metal ions in MRI contrast agent nanoparticles have the potential risk of disrupting the redox balance in vivo by reacting with hydrogen peroxide to produce reactive oxygen species (ROS), and oxidizing vitamins and proteins, which are antioxidants present in the body; this leads to the progression and development of the disease.…”

Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering

“…One study used hybrid metal oxide-peptide amphiphile micelles (HMO-Ms), which are designed to enable MRI imaging of thrombosis at atherosclerotic plaques through the fibrin-targeting sequence CREKA [ 178 ]. In vivo studies in a murine ApoE −/− plaque model using poly(maleicanhydride-alt-1-octadecene) (PMAO)-coated IONPs showed that the IONPs accumulated in similar vascular regions as an elastin-targeting gadolinium-based contrast agent which accumulated in plaques [ 179 ]. Kim et al compared the potency of the two targeting ligands, cRGD peptide and collagen IV, which binds to αvβ3-integrin overexpressed in neovasculature and collagen type IV present in plaque, respectively [ 180 ].…”

Progress and prospects of magnetic iron oxide nanoparticles in biomedical applications: A review

“…The SPIONs were conjugated with antibodies for targeted delivery. However, more investigations are proposed to explore the surface ligands 204 . Ultra‐small magnetic IONPs were synthesized via the co‐precipitation method and utilized for T1‐weighted MRI and chemotherapy of tumors by Chen and his coworkers.…”