Repeated Injection of Very Small Superparamagnetic Iron Oxide Particles (VSOPs) in Murine Atherosclerosis: A Safety Study.

Citrate-coated electrostatically stabilized very small superparamagnetic iron oxide particles (VSOPs) have been successfully tested as magnetic resonance angiography (MRA) contrast agents and are promising tools for molecular imaging of atherosclerosis. Their repeated use in the background of pre-existing hyperlipidemia and atherosclerosis has not yet been studied. This study aimed to investigate the effect of multiple intravenous injections of VSOPs in atherosclerotic mice. Taurine-formulated VSOPs (VSOP-T) were repeatedly intravenously injected at 100 µmol Fe/kg in apolipoprotein E-deficient (ApoE KO) mice with diet-induced atherosclerosis. Angiographic imaging was carried out by in vivo MRI. Magnetic particle spectrometry was used to detect tissue VSOP content, and tissue iron content was quantified photometrically. Pathological changes in organs, atherosclerotic plaque development, and expression of hepatic iron-related proteins were evaluated. VSOP-T enabled the angiographic imaging of heart and blood vessels with a blood half-life of one hour. Repeated intravenous injection led to VSOP deposition and iron accumulation in the liver and spleen without affecting liver and spleen pathology, expression of hepatic iron metabolism proteins, serum lipids, or atherosclerotic lesion formation. Repeated injections of VSOP-T doses sufficient for MRA analyses had no significant effects on plaque burden, steatohepatitis, and iron homeostasis in atherosclerotic mice. These findings underscore the safety of VSOP-T and support its further development as a contrast agent and molecular imaging tool.

Temperature dependent magnetorelaxometry of magnetic nanoparticle ensembles.

Magnetorelaxometry imaging (MRXI) is a non-invasive, quantitative imaging technique for magnetic nanoparticles (MNPs). The image resolution of this technique significantly depends on the relaxation amplitude (ΔB). For this work, we measured the room temperature (299 K) relaxation signals of eight commercial MNP sample systems with different magnetic properties, in both fluid and immobilized states, in order to select the most suitable sample for a particular MRXI setting. Additionally, the effect of elevated temperatures (up to hyperthermia temperature, 335 K) on the relaxation signals of four different MNP systems (Synomag, Perimag, BNF and Nanomag) in both states were investigated. The ΔBvalues of fluid samples significantly decreased with increasing temperature, and the behaviour for immobilized samples depended on their blocking temperature (TB). For samples withTB< 299 K, ΔBalso decreased with increasing temperature. Whereas for samples withTB> 299 K, the opposite behaviour was observed. These results are beneficial for improving the image resolution in MRXI and show, among the investigated systems, and for our setup, Synomag is the best candidate for futurein vitroandin vivostudies. This is due to its consistently high ΔBbetween 299 and 335 K in both states. Our findings demonstrate the feasibility of temperature imaging by MRXI.

Developing magnetorelaxometry imaging for human applications.

Objective.Magnetic nanoparticles (MNPs) are a promising tool in biomedical applications such as cancer therapy and diagnosis, where localization and quantification of MNP distributions are often mandatory. This can be obtained by magnetorelaxometry imaging (MRXI).Approach.In this work, the capability of MRXI for quantitative imaging of MNP inside larger volumes such as a human head is investigated. We developed a human head phantom simulating a glioblastoma multiforme (GBM) tumor containing MNP for magnetic hyperthermia treatment. The sensitivity of our MRXI setup for detection of MNP concentrations in the range of 3-19 mg cm-3was studied.Main result.The results show the high capability of MRXI to detect MNPs in a human head sized volume. Superficial sources with a concentration larger than 12 mg cm-3could be reconstructed with a resulotion of about 1 cm-3.Significance.The reconstruction of the MNP distribution, mimicking a GBM tumor of 7 cm3volume with clinically relevant iron concentration, demonstrates thein vivofeasibility of MRXI in humans.

Nanomagnetic Actuation of Hybrid Stents for Hyperthermia Treatment of Hollow Organ Tumors.

This paper describes a magnetic nanotechnology that locally enables hyperthermia treatment of hollow organ tumors by using polymer hybrid stents with incorporated magnetic nanoparticles (MNP). The hybrid stents are implanted and activated in an alternating magnetic field to generate therapeutically effective heat, thereby destroying the tumor. Here, we demonstrate the feasibility of nanomagnetic actuation of three prototype hybrid stents for hyperthermia treatment of hollow organ tumors. The results show that the heating efficiency of stent filaments increases with frequency from approximately 60 W/gFe (95 kHz) to approximately 250 W/gFe (270 kHz). The same trend is observed for the variation of magnetic field amplitude; however, heating efficiency saturates at approximately 30 kA/m. MNP immobilization strongly influences heating efficiency showing a relative difference in heating output of up to 60% compared to that of freely dispersed MNP. The stents showed uniformly distributed heat on their surface reaching therapeutically effective temperatures of 43 °C and were tested in an explanted pig bile duct for their biological safety. Nanomagnetic actuation of hybrid stents opens new possibilities in cancer treatment of hollow organ tumors.

Magnetic separation of iron oxide nanoparticles to improve their application for magnetic particle imaging.

Magnetic particle imaging (MPI) is a promising medical imaging technique for visualizing the three-dimensional distribution of tracer materials, specifically iron oxide nanoparticles (IONP). The optimization of magnetic nanoparticles (MNP) plays an essential role to improve the image resolution and sensitivity of imaging techniques. OBJECTIVE: In this work, the optimization of commercial IONP (EMG 700, Ferrotec) coated with anionic surfactants was carried out using magnetic separation (MS) technique, by a low gradient magnetic separation (LGMS) (<15 T m-1) method, to improve their performance as MPI tracers. APPROACH: The magnetophoretical behavior of the samples in different concentrations ranging from 2 to 120 mmol l-1 was investigated over 24 h of separation. The samples were characterized by dynamic light scattering (DLS), AC susceptibility (ACS), magnetic particle spectroscopy (MPS) and they were imaged in a preclinical MPI scanner, before and after MS. MAIN RESULTS: DLS results showed that by increasing the concentration from 2 to 120 mmol l-1 the hydrodynamic diameter of MNP decrease from 75 to 47 nm and size distribution decrease from 0.19 to 0.11 after 4 min MS. In addition, the MPS results demonstrated the third harmonic amplitude normalized to the iron amount [Formula: see text] and harmonic ratio [Formula: see text] of signal increase from 8.38 to 10.59 Am2 kg-1 (Fe) and 24.21-26.60, respectively. Furthermore, the MPI images of the samples after separation showed higher MPI resolution. SIGNIFICANCE: Therefore, LGMS can be considered as a valuable method to narrow and control the size distribution of MNP for MPI.

Investigation of magnetically driven passage of magnetic nanoparticles through eye tissues for magnetic drug targeting.

This paper elucidates the feasibility of magnetic drug targeting to the eye by using magnetic nanoparticles (MNPs) to which pharmaceutical drugs can be linked. Numerical simulations revealed that a magnetic field gradient of 20 T m-1 seems to be promising for dragging magnetic multicore nanoparticles of about 50 nm into the eye. Thus, a targeting magnet system made of superconducting magnets with a magnetic field gradient at the eye of about 20 T m-1 was simulated. For the proof-of-concept tissue experiments presented here the required magnetic field gradient of 20 T m-1 was realized by a permanent magnet array. MNPs with an optimized multicore structure were selected for this application by evaluating their stability against agglomeration of MNPs with different coatings in water for injections, physiological sodium chloride solution and biological media such as artificial tear fluid. From these investigations, starch turned out to be the most promising coating material because of its stability in saline fluids due to its steric stabilization mechanism. To evaluate the passage of MNPs through the sclera and cornea of the eye tissues of domestic pigs (Sus scrofa domesticus), a three-dimensionally printed setup consisting of two chambers (reservoir and target chamber) separated by the eye tissue was developed. With the permanent magnet array emulating the magnetic field gradient of the superconducting setup, experiments on magnetically driven transport of the MNPs from the reservoir chamber into the target chamber via the tissue were performed. The resulting concentration of MNPs in the target chamber was determined by means of quantitative magnetic particle spectroscopy. It was found that none of the tested particles passed the cornea, but starch-coated particles could pass the sclera at a rate of about 5 ng mm-2 within 24 h. These results open the door for future magnetic drug targeting to the eye.

Noninvasive monitoring of blood flow using a single magnetic microsphere.

Noninvasive medical imaging of blood flow relies on mapping the transit of a contrast medium bolus injected intravenously. This has the draw-back that the front of the bolus widens until the tissue of interest is reached and quantitative flow parameters are not easy to obtain. Here, we introduce high resolution (millimeter/millisecond) 3D magnetic tracking of a single microsphere locally probing the flow while passing through a vessel. With this, we successfully localize and evaluate diameter constrictions in an arteria phantom after a single passage of a microsphere. We further demonstrate the potential for clinical application by tracking a microsphere smaller than a red blood cell.

Selection of potential iron oxide nanoparticles for breast cancer treatment based on in vitro cytotoxicity and cellular uptake.

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising tools for the treatment of different diseases. Their magnetic properties enable therapies involving magnetic drug targeting (MDT), hyperthermia or imaging. Depending on the intended treatment, specific characteristics of SPIONs are required. While particles used for imaging should circulate for extended periods of time in the vascular system, SPIONs intended for MDT or hyperthermia should be accumulated in the target area to come into close proximity of, or to be incorporated into, specific tumor cells. In this study, we determined the impact of several accurately characterized SPION types varying in size, zeta potential and surface coating on various human breast cancer cell lines and endothelial cells to identify the most suitable particle for future breast cancer therapy. We analyzed cellular SPION uptake, magnetic properties, cell proliferation and toxicity using atomic emission spectroscopy, magnetic susceptometry, flow cytometry and microscopy. The results demonstrated that treatment with dextran-coated SPIONs (SPIONDex) and lauric acid-coated SPIONs (SPIONLA) with an additional protein corona formed by human serum albumin (SPIONLA-HSA) resulted in very moderate particle uptake and low cytotoxicity, whereas SPIONLA had in part much stronger effects on cellular uptake and cellular toxicity. In summary, our data show significant dose-dependent and particle type-related response differences between various breast cancer and endothelial cells, indicating the utility of these particle types for distinct medical applications.

Magnetorelaxometry procedures for quantitative imaging and characterization of magnetic nanoparticles in biomedical applications.

BACKGROUND: Quantitative knowledge about the spatial distribution and local environment of magnetic nanoparticles (MNPs) inside an organism is essential for guidance and improvement of biomedical applications such as magnetic hyperthermia and magnetic drug targeting. Magnetorelaxometry (MRX) provides such quantitative information by detecting the magnetic response of MNPs following a fast change in the applied magnetic field. METHODS: In this article, we review our MRX based procedures that enable both the characterization and the quantitative imaging of MNPs in a biomedical environment. RESULTS: MRX characterization supported the selection of an MNP system with colloidal stability and suitable cellular MNP uptake. Spatially resolved MRX, a procedure employing multi-channel MRX measurements allowed for in-vivo monitoring of the MNP distribution in a pre-clinical carcinoma animal model. Extending spatially resolved MRX by consecutive magnetization of distinct parts of the sample led to a demonstration of MRX tomography. With this tomography, we reconstructed the three dimensional MNP distribution inside animal sized phantoms with a sensitivity of milligrams of MNPs per cm3. In addition, the targeting efficiency of MNPs in whole blood was assessed using a flow phantom and MRX quantification. CONCLUSION: These MRX based measurement and analysis procedures have substantially supported the development of MNP based biomedical applications.