MPI Phantom Study with A High-Performing Multicore Tracer Made by Coprecipitation

Magnetic particle imaging (MPI) is a new imaging technique that detects the spatial distribution of magnetic nanoparticles (MNP) with the option of high temporal resolution. MPI relies on particular MNP as tracers with tailored characteristics for improvement of sensitivity and image resolution. For this reason, we developed optimized multicore particles (MCP 3) made by coprecipitation via synthesis of green rust and subsequent oxidation to iron oxide cores consisting of a magnetite/maghemite mixed phase. MCP 3 shows high saturation magnetization close to that of bulk maghemite and provides excellent magnetic particle spectroscopy properties which are superior to Resovist® and any other up to now published MPI tracers made by coprecipitation. To evaluate the MPI characteristics of MCP 3 two kinds of tube phantoms were prepared and investigated to assess sensitivity, spatial resolution, artifact severity, and selectivity. Resovist® was used as standard of comparison. For image reconstruction, the regularization factor was optimized, and the resulting images were investigated in terms of quantifying of volumes and iron content. Our results demonstrate the superiority of MCP 3 over Resovist® for all investigated MPI characteristics and suggest that MCP 3 is promising for future experimental in vivo studies

Magnetic Particle Imaging: Neue Ansätze für die Gefäßbildgebung

Magnetic Particle Imaging (MPI) is a relatively new medical imaging modality that is currently (as of 2020) in experimental phase. MPI utilizes the unique magnetic properties of magnetic nanoparticles (MNP) and visualizes the MNP distribution as three-dimensional maps. MNP characteristics, alongside the intrinsic parameters of the instrumental scanner, determine the spatial resolution, sensitivity and image quality of MPI. Therefore, the development of optimized MPI tracers is crucial for advancement of the imaging technique and to identify potential applications in diagnostic imaging. Multicore nanoparticles (MCP) tailored for MPI were synthesized in our lab, and their MPI performance was evaluated in comparison to Resovist in phantoms, single or double tubes, and in vivo. For the in vivo angiography study, 8 healthy rats were examined in 16 examinations. The inferior vena cava (IVC) and abdominal aorta (AA) were imaged in a 2 cm suprarenal segment after i.v. injection of MCP and Resovist in 3 dosages of 0.1, 0.05 and 0.025 mmol Fe/kg. In a further study, the vascular inflammation in abdominal aortic aneurysms (AAA) induced in Apolipoprotein E-deficient-mice (n=32) was imaged with MPI ex vivo, 24 h post i.v. Resovist injection (dosage 46.66 μg Fe/kg). The results were validated by histology and magnetic particle spectroscopy (MPS). Moreover, the blood half-life (t1/2) of modified MCP, surface coated with Polyethylene glycol (PEG), using MRI was investigated. MCP, compared to Resovist, provided higher signal-to-noise ratio in MPI, a finer spatial resolution of 1 mm or even lower, higher sensitivity, with successful visualization of 0.1 mmol Fe/l concentration in phantoms, and a distinctive qualitative outcome in in vivo MPI angiographic studies. After administration of MCP at dosages of 0.1, 0.05 mmol Fe/kg, the vessel lumen diameters (DL) of IVC and AA could be assessed with IVC=2.7 ± 0.6 and of AA=2.4 ± 0.7 mm. The accumulation of Resovist in inflammatory cells of AAA was imaged ex vivo quantitively in MPI and verified by Prussian blue and anti-CD86 immunohistochemistry. The iron amount quantification results correlated with MPS results (R=0.99). The successful PEGylation of MCP led to prolongation of t1/2 from several minutes to over an hour. Overall, MCP showed superior MPI image quality. The results implied that angiographic and cellular imaging of vascular abnormalities such as aneurysm is feasible with MPI, with the simultaneous quantitative measurement of MNP concentration. MPI is an evolving technology, with a good prospect as a clinical diagnostic tool. The findings in the presented work underline the current possibilities, challenges and limitations of MPI for experimental in vivo imaging with the perspective towards potential future clinical applications.Magnetic Particle Imaging (MPI) ist eine relativ neue medizinische Bildgebungsmodalität, die sich derzeit (Stand 2020) in der experimentellen Phase befindet. MPI nutzt die einzigartigen Eigenschaften magnetischer Nanopartikel (MNP) und visualisiert die MNP-Verteilung dreidimensional. Neben den intrinsischen Parametern des Scanners bestimmen die MNP Eigenschaften die räumliche Auflösung, die Empfindlichkeit und die Bildqualität von MPI. Daher ist die Entwicklung optimierter MPI-Tracer entscheidend für die Weiterentwicklung dieser Bildgebungstechnik und die Identifizierung potenzieller Anwendungen in der diagnostischen Bildgebung. In unserem Labor wurden auf MPI optimierte Multicore-Nanopartikel (MCP) synthetisiert und ihre MPI-Leistung in Phantomen und in vivo im Vergleich zu Resovist bewertet. Die In-vivo- Angiographiestudie wurden an 8 gesunden Ratten in 16 Untersuchungen durchgeführt. Nach i.v.-Injektion von MCP und Resovist in den Dosierungen 0.1, 0.05 und 0.025 mmol Fe/kg wurden die Vena cava inferior (IVC) und die abdominale Aorta (AA) suprarenal in einem 2 cm langen Segment abgebildet. In einer weiteren Studie wurde die vaskuläre Entzündung in der Wand von induzierten abdominalen Aortenaneurysmen (AAA) in ApoE-/- Mäusen (n=32) 24 h nach i.v.-Resovist-Injektion abgebildet (Dosierung 46.66 μg Fe/kg). Die Ergebnisse wurden durch Histologie und Magnetic Particle Spectroscopy (MPS) validiert. Darüber hinaus wurde die Bluthalbwertszeit (t1/2) von PEG-modifizierten MCP mittels MRT untersucht. MCP lieferten im MPI im Vergleich zu Resovist ein höheres Signal-Rausch-Verhältnis, eine höhere räumliche Auflösung von unter 1 mm, eine höhere Sensitivität bei erfolgreicher Visualisierung der 0.1 mmol Fe/l in Phantomen und ein qualitativ besseres Ergebnis in in-vivo- MPI-Angiographiestudien. Nach Verabreichung von MCP in den Dosierungen 0.1 und 0.05 mmol Fe/kg konnten die Gefäßlumendurchmesser von IVC = 2,7±0,6 mm und AA = 2,4±0,7 mm berechnet werden. In entzündlichen Zellen des abdominalen AAA konnte ex vivo die Akkumulation von Resovist quantitativ im MPI abgebildet und durch Berliner Blau- Färbung und Anti-CD86-Immunhistochemie verifiziert werden. Die Ergebnisse der Eisenmengenquantifizierung korrelierten mit den MPS-Ergebnissen (R=0,99). Die erfolgreiche PEGylierung von MCP führte zu einer Verlängerung von t1/2 wenigen Minuten auf über eine Stunde. Insgesamt zeigte MCP eine überlegene MPI-Bildqualität. Die Ergebnisse implizieren, dass eine angiographische und zelluläre Bildgebung von Gefäßanomalien wie Aneurysmen bei gleichzeitiger quantitativer Messung der MNP-Konzentration mit MPI möglich ist. MPI ist eine sich weiterentwickelnde Technologie mit Potenzial für die klinische Diagnostik. Die Ergebnisse der vorgestellten Arbeit unterstreichen die aktuellen Möglichkeiten, Herausforderungen und Grenzen des MPI für die experimentelle in-vivo-Bildgebung in Hinblick auf mögliche zukünftige klinische Anwendungen

In vivo magnetic particle imaging: angiography of inferior vena cava and aorta in rats using newly developed multicore particles

Magnetic Particle Imaging (MPI) is a new imaging modality, which maps the distribution of magnetic nanoparticles (MNP) in 3D with high temporal resolution. It thus may be suited for cardiovascular imaging. Its sensitivity and spatial resolution critically depend on the magnetic properties of MNP. Therefore, we used novel multicore nanoparticles (MCP 3) for in-vivo MPI in rats and analyzed dose requirements, sensitivity and detail resolution. 8 rats were examined using a preclinical MPI scanner (Bruker Biospin GmbH, Germany) equipped with a separate receive coil. MCP 3 and Resovist were administered intravenously (i.v.) into the rats’ tail veins at doses of 0.1, 0.05 and 0.025 mmol Fe/kg followed by serial MPI acquisition with a temporal resolution of 46 volumes per second. Based on a qualitative visual scoring system MCP 3–MPI images showed a significantly (P ≤ 0.05) higher image quality than Resovist-MPI images. Morphological features such as vessel lumen diameters (DL) of the inferior vena cava (IVC) and abdominal aorta (AA) could be assessed along a 2-cm segment in mesenteric area only after administration of MCP 3 at dosages of 0.1, 0.05 mmol Fe/kg. The mean DL ± SD estimated was 2.7 ± 0.6 mm for IVC and 2.4 ± 0.7 mm for AA. Evaluation of DL of the IVC and AA was not possible in Resovist-MPI images. Our results show, that MCP 3 provide better image quality at a lower dosage than Resovist. MCP 3-MPI with a clinically acceptable dose of 0.05 mmol Fe/kg increased the visibility of vessel lumens compared to Resovist-based MPI towards possible detection of vascular abnormalities such as stenosis or aneurysms, in vivo

Tailored Magnetic Multicore Nanoparticles for Use as Blood Pool MPI Tracers

For the preclinical development of magnetic particle imaging (MPI) in general, and the exploration of possible new clinical applications of MPI in particular, tailored MPI tracers with surface properties optimized for the intended use are needed. Here we present the synthesis of magnetic multicore particles (MCPs) modified with polyethylene glycol (PEG) for use as blood pool MPI tracers. To achieve the stealth effect the carboxylic groups of the parent MCP were activated and coupled with pegylated amines (mPEG-amines) with different PEG-chain lengths from 2 to 20 kDa. The resulting MCP-PEG variants with PEG-chain lengths of 10 kDa (MCP-PEG10K after one pegylation step and MCP-PEG10K2 after a second pegylation step) formed stable dispersions and showed strong evidence of a successful reaction of MCP and MCP-PEG10K with mPEG-amine with 10 kDa, while maintaining their magnetic properties. In rats, the mean blood half-lives, surprisingly, were 2 and 62 min, respectively, and therefore, for MCP-PEG10K2, dramatically extended compared to the parent MCP, presumably due to the higher PEG density on the particle surface, which may lead to a lower phagocytosis rate. Because of their significantly extended blood half-life, MCP-PEG10K2 are very promising as blood pool tracers for future in vivo cardiovascular MPI

Magnetic particle imaging of vascular inflammation in abdominal aortic aneurysm in murine model

Abdominal aortic aneurysm (AAAs) is a vascular disease, currently one of the leading causes of death in developed countries. Vascular inflammation plays a crucial role in the disease progression and substantially impacts many determinants in AAAs advancement. Superparamagnetic iron oxide nanoparticles (SPION)  have been shown to be suitable agents for molecular targeting of vascular inflammation. The quantitative ability of MPI in mapping of SPION makes MPI a valid tool for monitoring of AAA progression. In this study, we examined the feasibility of MPI for imaging vascular inflammation in AAA in Angiotensin II-infused ApoE-/- mice with MPI suitable SPION, ferucarbotran (Resovist ®). The results were validated by histological analysis and magnetic particle spectroscopy (MPS)

Ex vivo magnetic particle imaging of vascular inflammation in abdominal aortic aneurysm in a murine model

Abdominal aortic aneurysms (AAAs) are currently one of the leading causes of death in developed countries. Inflammation is crucial in the disease progression, having a substantial impact on various determinants in AAAs development. Magnetic particle imaging (MPI) is an innovative imaging modality, enabling the highly sensitive detection of magnetic nanoparticles (MNPs), suitable as surrogate marker for molecular targeting of vascular inflammation. For this study, Apolipoprotein E-deficient-mice underwent surgical implantation of osmotic minipumps with constant Angiotensin II infusion. After 3 and 4 weeks respectively, in-vivo-magnetic resonance imaging (MRI), ex-vivo-MPI and ex-vivo-magnetic particle spectroscopy (MPS) were performed. The results were validated by histological analysis, immunohistology and laser ablation-inductively coupled plasma-mass spectrometry. MR-angiography enabled the visualization of aneurysmal development and dilatation in the experimental group. A close correlation (R = 0.87) with histological area assessment was measured. Ex-vivo-MPS revealed abundant iron deposits in AAA samples and ex-vivo histopathology measurements were in good agreement (R = 0.76). Ex-vivo-MPI and MPS results correlated greatly (R = 0.99). CD68-immunohistology stain and Perls’-Prussian-Blue-stain confirmed the colocalization of macrophages and MNPs. This study demonstrates the feasibility of ex-vivo-MPI for detecting inflammation in AAA. The quantitative ability for mapping MNPs establishes MPI as a promising tool for monitoring inflammatory progression in AAA in an experimental setting