Iron Speciation in Animal Tissues Using AC Magnetic Susceptibility Measurements: Quantification of Magnetic Nanoparticles, Ferritin, and Other Iron-Containing Species.

The simultaneous detection and quantification of several iron-containing species in biological matrices is a challenging issue. Especially in the frame of studies using magnetic nanoparticles for biomedical applications, no gold-standard technique has been described yet and combinations of different techniques are generally used. In this work, AC magnetic susceptibility measurements are used to analyze different organs from an animal model that received a single intratumor administration of magnetic nanoparticles. The protocol used for the quantification of iron associated with the magnetic nanoparticles is carefully described, including the description of the preparation of several calibration standard samples of nanoparticle suspensions with different degrees of dipolar interactions. The details for the quantitative analysis of other endogenous iron-containing species such as ferritin or hemoglobin are also described. Among the advantages of this technique are that tissue sample preparation is minimal and that large amounts of tissue can be characterized each time (up to hundreds of milligrams). In addition, the very high specificity of the magnetic measurements allows for tracking of the nanoparticle transformations. Furthermore, the high sensitivity of the instrumentation results in very low limits of detection for some of the iron-containing species. Therefore, the presented technique is an extremely valuable tool to track iron oxide magnetic nanoparticles in samples of biological origin.

Effects of magnetite nanoparticles on physiological processes to alleviate salinity induced oxidative damage in wheat.

BACKGROUND: One of the major abiotic stressors that have a serious effect on plant growth and productivity worldwide is the salinity of soil or irrigation water. The effect of foliar application of magnetite nanoparticles (size = 22.05 nm) at different concentrations (0, 0.25, 0.5, and 1.0 ppm) was investigated to improve salinity tolerance in two wheat cultivars, namely, Misr1 (Tolerant) and Gimmeza11 (Sensitive). Moreover, toxicological investigations of magnetite oxide nanoparticle in Wistar albino rats were estimated. RESULTS: The magnetite nanoparticles positively affected growth, chlorophyll, and enzymatic antioxidants such as superoxide dismutase (SOD), stimulating reduced glutathione and improving the aggregation of several polypeptide chains that may be linked to the tolerance of saline stress. In contrast, magnetite nanoparticles reduced malondialdehyde (MDA). Inverse sequence-tagged repeat (ISTR) assay of DNA molecular marker showed the change in band numbers with the highest polymorphic bands with 90% polymorphism at primer F3, B5 and 20 positive bands in Gimmeza11 with 0.5 ppm magnetite nanoparticles. In the median lethal dose (LD50 ) study, no rats died after the oral administration of magnetite nanoparticle at different doses. Therefore, the iron oxide nanoparticle was nontoxic when administered orally by gavage. CONCLUSION: Magnetite nanoparticles partially helped to alleviate the effects of salt stress by activating growth, chlorophyll content, SOD, glutathione, and soluble proteins in two wheat cultivars (Misr1 and Gimmeza11) and decreasing MDA content. © 2021 Society of Chemical Industry.

High sensitive detection of circulating tumor cell by multimarker lipid magnetic nanoparticles and clinical verifications.

Tumor cells with heterogeneity and diversity can express different markers. At present, positive separation of circulating tumor cells (CTC) taking EpCAM as the marker was used in most cases which could be one-sided, while this study successfully prepared four antibody-modified magnetic immunoliposomes (MIL) by using the self-assembled liposome with antibody derivatives. This study aims to explore the separation efficiency and clinical detection feasibility of single or combined use of MIL with multi-tumor markers on different tumors. Captured CTC were stained with CK-FITC, CD45-PE and DAPI, and fluorescence microscope was used for the observation, analysis and calculation. The result indicated that the CTC number positive rate in blood samples of four different magnetic balls on the same patient could be up to 87.5% in 32 patients with 14 different kinds tumors. While the effect of directly mixed separation by four kinds of magnetic balls was not satisfying. It suggested that the MIL of multi-tumor markers could be a powerful tool for CTC separation in application of tumor screening and prognosis.

Therapeutic potential of low-cost nanocarriers produced by green synthesis: macrophage uptake of superparamagnetic iron oxide nanoparticles.

Aim: The primary goal of this work was to synthesize low-cost superparamagnetic iron oxide nanoparticles (SPIONs) with the aid of coconut water and evaluate the ability of macrophages to internalize them. Our motivation was to determine potential therapeutic applications in drug-delivery systems associated with magnetic hyperthermia. Materials & methods: We used the following characterization techniques: x-ray and electron diffractions, electron microscopy, spectrometry and magnetometry. Results: The synthesized SPIONs, roughly 4 nm in diameter, were internalized by macrophages, likely via endocytic/phagocytic pathways. They were randomly distributed throughout the cytoplasm and mainly located in membrane-bound compartments. Conclusion: Nanoparticles presented an elevated intrinsic loss power value and were not cytotoxic to mammalian cells. Thus, we suggest that low-cost SPIONs have great therapeutic potential.

Dual-modality imaging of atherosclerotic plaques using ultrasmall superparamagnetic iron oxide labeled with rhodamine.

Aim: The diagnosis of vulnerable atherosclerotic plaques remains challenging. This study labeled ultrasmall superparamagnetic iron oxide with rhodamine (USPIO-R) and evaluated USPIO-R for imaging atherosclerotic plaques. Methods: Apolipoprotein E-deficient mice were fed a high-fat diet and underwent MRI before and after an intravenous injection of USPIO-R. Subsequently, an aortic specimen from the mice was removed and sliced for fluorescence imaging and Prussian blue and immunofluorescent staining. Results: T2 signal loss appeared and persisted in the aortic plaque postinjection, and spontaneous fluorescence from the plaque was observed. The accumulated mechanism of USPIO-R by plaque was the macrophage internalization by Prussian blue and immunofluorescence. Conclusion: USPIO-R is a promising dual-modality probe for diagnosing and monitoring vulnerable atherosclerotic plaques.

Optimization and Design of Magnetic Ferrite Nanoparticles with Uniform Tumor Distribution for Highly Sensitive MRI/MPI Performance and Improved Magnetic Hyperthermia Therapy.

Two major technical challenges of magnetic hyperthermia are quantitative assessment of agent distribution during and following administration and achieving uniform heating of the tumor at the desired temperature without damaging the surrounding tissues. In this study, we developed a multimodal MRI/MPI theranostic agent with active biological targeting for improved magnetic hyperthermia therapy (MHT). First, by systematically elucidating the magnetic nanoparticle magnetic characteristics and the magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) signal enhancement effects, which are based on the magnetic anisotropy, size, and type of nanoparticles, we found that 18 nm iron oxide NPs (IOs) could be used as superior nanocrystallines for high performance of MRI/MPI contrast agents in vitro. To improve the delivery uniformity, we then targeted tumors with the 18 nm IOs using a tumor targeting peptide, CREKA. Both MRI and MPI signals showed that the targeting agent improves the intratumoral delivery uniformity of nanoparticles in a 4T1 orthotopic mouse breast cancer model. Lastly, the in vivo antitumor MHT effect was evaluated, and the data showed that the improved targeting and delivery uniformity enables more effective magnetic hyperthermia cancer ablation than otherwise identical, nontargeting IOs. This preclinical study of image-guided MHT using cancer-targeting IOs and a novel MPI system paves the way for new MHT strategies.

Biodistribution of Glial Progenitors in a Three Dimensional-Printed Model of the Piglet Cerebral Ventricular System.

White matter damage persists in hypoxic-ischemic newborns even when treated with hypothermia. We have previously shown that intraventricular delivery of human glial progenitors (GPs) at the neonatal stage is capable of replacing abnormal host glia and rescuing the lifespan of dysmyelinated mice. However, such transplantation in the human brain poses significant challenges as related to high-volume ventricles and long cell migration distances. These challenges can only be studied in large animal model systems. In this study, we developed a three dimensional (3D)-printed model of the ventricular system sized to a newborn pig to investigate the parameters that can maximize a global biodistribution of injected GPs within the ventricular system, while minimizing outflow to the subarachnoid space. Bioluminescent imaging and magnetic resonance imaging were used to image the biodistribution of luciferase-transduced GPs in simple fluid containers and a custom-designed, 3D-printed model of the piglet ventricular system. Seven independent variables were investigated. The results demonstrated that a low volume (0.1 mL) of cell suspension is essential to keep cells within the ventricular system. If higher volumes (1 mL) are needed, a very slow infusion speed (0.01 mL/min) is necessary. Real-time magnetic resonance imaging demonstrated that superparamagnetic iron oxide (SPIO) labeling significantly alters the rheological properties of the GP suspension, such that, even at high speeds and high volumes, the outflow to the subarachnoid space is reduced. Several other factors, including GP species (human vs. mouse), type of catheter tip (end hole vs. side hole), catheter length (0.3 vs. 7.62 m), and cell concentration, had less effect on the overall distribution of GPs. We conclude that the use of a 3D-printed phantom model represents a robust, reproducible, and cost-saving alternative to in vivo large animal studies for determining optimal injection parameters.

Promoting the Delivery of Nanoparticles to Atherosclerotic Plaques by DNA Coating.

Many nanoparticle-based carriers to atherosclerotic plaques contain peptides, lipoproteins, and sugars, yet the application of DNA-based nanostructures for targeting plaques remains infrequent. In this work, we demonstrate that DNA-coated superparamagnetic iron oxide nanoparticles (DNA-SPIONs), prepared by attaching DNA oligonucleotides to poly(ethylene glycol)-coated SPIONs (PEG-SPIONs), effectively accumulate in the macrophages of atherosclerotic plaques following an intravenous injection into apolipoprotein E knockout (ApoE-/-) mice. DNA-SPIONs enter RAW 264.7 macrophages faster and more abundantly than PEG-SPIONs. DNA-SPIONs mostly enter RAW 264.7 cells by engaging Class A scavenger receptors (SR-A) and lipid rafts and traffic inside the cell along the endolysosomal pathway. ABS-SPIONs, nanoparticles with a similarly polyanionic surface charge as DNA-SPIONs but bearing abasic oligonucleotides also effectively bind to SR-A and enter RAW 264.7 cells. Near-infrared fluorescence imaging reveals evident localization of DNA-SPIONs in the heart and aorta 30 min post-injection. Aortic iron content for DNA-SPIONs climbs to the peak (∼60% ID/g) 2 h post-injection (accompanied by profuse accumulation in the aortic root), but it takes 8 h for PEG-SPIONs to reach the peak aortic amount (∼44% ID/g). ABS-SPIONs do not appreciably accumulate in the aorta or aortic root, suggesting that the DNA coating (not the surface charge) dictates in vivo plaque accumulation. Flow cytometry analysis reveals more pronounced uptake of DNA-SPIONs by hepatic endothelial cells, splenic macrophages and dendritic cells, and aortic M2 macrophages (the cell type with the highest uptake in the aorta) than PEG-SPIONs. In summary, coating nanoparticles with DNA is an effective strategy of promoting their systemic delivery to atherosclerotic plaques.

Modelling of magnetoimpedance response of thin film sensitive element in the presence of ferrogel: Next step toward development of biosensor for in-tissue embedded magnetic nanoparticles detection.

In-tissue embedded magnetic nanoparticle (MNPs) detection is one of the most interesting cases for cancer research. In order to understand the origin, the limits and the way of improvement of magnetic biosensor sensitivity for the detection of 3D mezoscopic distributions of MNPs, we have developed a magnetoimpedance biosensor prototype with a [Cu (3 nm)/FeNi(100 nm)]5/Cu(500 nm)/[FeNi(100 nm)/Cu(3 nm)]5 rectangular sensitive element. Magnetoimpedance (MI) responses were measured with and without polyacrylamide ferrogel layer mimicking natural tissue in order to evaluate stray fields of embedded MNPs of γ-Fe2O3 iron oxide. A model for MI response based on a solution of Maxwell equations with Landau-Lifshitz equation was developed in order to understand the origin of the prototype sensitivity which reached 1.3% of ΔZ/Z per 1% of MNPs concentration by weight. To make this promising technique useful for magnetically labeled tissue detection, a synthesis of composite gels with MNPs agglomerates compactly located inside pure gel and their MI testing are still necessary.

Magnetic particle imaging for radiation-free, sensitive and high-contrast vascular imaging and cell tracking.

Magnetic particle imaging (MPI) is an emerging ionizing radiation-free biomedical tracer imaging technique that directly images the intense magnetization of superparamagnetic iron oxide nanoparticles (SPIOs). MPI offers ideal image contrast because MPI shows zero signal from background tissues. Moreover, there is zero attenuation of the signal with depth in tissue, allowing for imaging deep inside the body quantitatively at any location. Recent work has demonstrated the potential of MPI for robust, sensitive vascular imaging and cell tracking with high contrast and dose-limited sensitivity comparable to nuclear medicine. To foster future applications in MPI, this new biomedical imaging field is welcoming researchers with expertise in imaging physics, magnetic nanoparticle synthesis and functionalization, nanoscale physics, and small animal imaging applications.

Dynamical Magnetic Response of Iron Oxide Nanoparticles Inside Live Cells.

Magnetic nanoparticles exposed to alternating magnetic fields have shown a great potential acting as magnetic hyperthermia mediators for cancer treatment. However, a dramatic and unexplained reduction of the nanoparticle magnetic heating efficiency has been evidenced when nanoparticles are located inside cells or tissues. Recent studies suggest the enhancement of nanoparticle clustering and/or immobilization after interaction with cells as possible causes, although a quantitative description of the influence of biological matrices on the magnetic response of magnetic nanoparticles under AC magnetic fields is still lacking. Here, we studied the effect of cell internalization on the dynamical magnetic response of iron oxide nanoparticles (IONPs). AC magnetometry and magnetic susceptibility measurements of two magnetic core sizes (11 and 21 nm) underscored differences in the dynamical magnetic response following cell uptake with effects more pronounced for larger sizes. Two methodologies have been employed for experimentally determining the magnetic heat losses of magnetic nanoparticles inside live cells without risking their viability as well as the suitability of magnetic nanostructures for in vitro hyperthermia studies. Our experimental results-supported by theoretical calculations-reveal that the enhancement of intracellular IONP clustering mainly drives the cell internalization effects rather than intracellular IONP immobilization. Understanding the effects related to the nanoparticle transit into live cells on their magnetic response will allow the design of nanostructures containing magnetic nanoparticles whose dynamical magnetic response will remain invariable in any biological environments, allowing sustained and predictable in vivo heating efficiency.

Magnetic iodixanol - a novel contrast agent and its early characterization.

AIMS: Contrast-induced nephropathy is a commonly encountered problem in clinical practice. The purpose of the study was to design and develop a novel contrast agent, which could be used to prevent contrast-induced nephropathy in the future. METHODS: In total, 20-220nm magnetic nanoparticles were conjugated with iodixanol, and their radio-opacity and magnetic properties were assessed thereafter. Scanning electron microscopy pictures were acquired. Thereafter, the nanoparticles conjugate was tested in cell culture (HUVEC cells), and Quantibody® assay was studied after cell treatment in 1:5 dilutions for 48h, compared with control. RESULTS: The conjugate preparation had an adequate radio-opacity. A 4mm magnetic bubble was attached to a bar magnet and the properties were studied. The magnetic bubble maintained its structural integrity in all angles including antigravity position. Scanning electron microscopy showed magnetic nanoparticles in all pictures and the particles are of 100-400nm agglomerates with primary particle sizes of roughly 20nm. 1:5 diluted particles had no effect on secretion of IL-1a, IL-1b, IL-4, IL-10, IL-13 and TNFa. Particles increased secretion of IL-8 from 24h and 48h. Secretion of IFNg was also increased when particles were added to the cells as early as 1h. Likewise, IL-6 was strongly secreted by HUVEC treated with particles from 24h incubation time. In contrast, the secretion of MCP-1 was slightly reduced on HUVEC treated with particles. CONCLUSION: There is potential for a novel iodixanol-magnetic nanoparticle conjugate to be used in cineradiography. Further investigations need to be performed to study its performance in vitro and in vivo.

Non-invasive monitoring of in vivo hydrogel degradation and cartilage regeneration by multiparametric MR imaging.

Numerous biodegradable hydrogels for cartilage regeneration have been widely used in the field of tissue engineering. However, to non-invasively monitor hydrogel degradation and efficiently evaluate cartilage restoration in situ is still challenging. Methods: A ultrasmall superparamagnetic iron oxide (USPIO)-labeled cellulose nanocrystal (CNC)/silk fibroin (SF)-blended hydrogel system was developed to monitor hydrogel degradation during cartilage regeneration. The physicochemical characterization and biocompatibility of the hydrogel were evaluated in vitro. The in vivo hydrogel degradation and cartilage regeneration of different implants were assessed using multiparametric magnetic resonance imaging (MRI) and further confirmed by histological analysis in a rabbit cartilage defect model for 3 months. Results: USPIO-labeled hydrogels showed sufficient MR contrast enhancement and retained stability without loss of the relaxation rate. Neither the mechanical properties of the hydrogels nor the proliferation of bone-marrow mesenchymal stem cells (BMSCs) were affected by USPIO labeling in vitro. CNC/SF hydrogels with BMSCs degraded more quickly than the acellular hydrogels as reflected by the MR relaxation rate trends in vivo. The morphology of neocartilage was noninvasively visualized by the three-dimensional water-selective cartilage MRI scan sequence, and the cartilage repair was further demonstrated by macroscopic and histological observations. Conclusion: This USPIO-labeled CNC/SF hydrogel system provides a new perspective on image-guided tissue engineering for cartilage regeneration.

Recent Advances in Superparamagnetic Iron Oxide Based Nanoprobes as Multifunctional Theranostic Agents for Breast Cancer Imaging and Therapy.

BACKGROUND: Breast cancer accounts for nearly one in three cancers, and it is the most common cancer diagnosed among women. The death rate of breast cancer is estimated to be 14%. Hence, accurate diagnosis in early stage and effective treatment in any stage are critical for the survival of breast cancer. Mammogram has been the most common technique administered to detect breast cancer. However, the radiation dose from mammogram is harmful to patients. Fortunately, magnetic resonance imaging (MRI) can diagnose breast cancer without any radiation dose, and enhanced MRI can make earlier and differential diagnosis. Therefore, as contrast materials, superparamagnetic iron oxide based nanoprobes (SPIONs) have generated a great deal of attention. OBJECTIVE: This review covers recent advances in SPIONs as multifunctional theranostic agents. METHODS: Besides synthesis and surface modification of SPIONs, passive and active targeted imaging is also discussed. Moreover, a serial of potential therapy for breast cancer is further described, such as photodynamic therapy, photothermal therapy, chemotherapy and magnetic hyperthermia therapy. CONCLUSION: Preparation and surface modification of SPIONs is critical for imaging diagnosis of breast cancer and further potential treatment.

Integrated microHall magnetometer to measure the magnetic properties of nanoparticles.

Magnetic nanoparticles (MNPs) are widely used in biomedical and clinical applications, including medical imaging, therapeutics, and biological sample processing. Rapid characterization of MNPs, notably their magnetic moments, should facilitate optimization of particle synthesis and accelerate assay development. Here, we report a compact and low-cost magnetometer for fast, on-site MNP characterization. Termed integrated microHall magnetometer (iHM), our device was fabricated using standard semiconductor processes: an array of Hall sensors, transistor switches, and amplifiers were integrated into a single chip, thus improving the detection sensitivity and facilitating chip operation. By applying the iHM, we demonstrate versatile magnetic assays. We measured the magnetic susceptibility and moments of MNPs using small sample amounts (∼10 pL), identified different MNP compositions in mixtures, and detected MNP-labeled single cells.

A reliable protocol for colorimetric determination of iron oxide nanoparticle uptake by cells.

Size, shape, and surface properties of superparamagnetic iron oxide nanoparticles (SPIONs) can influence their interaction with biological systems, particularly the incorporation by tumor cells and consequently the biological activity and efficiency in biomedical applications. Several strategies have been used to evaluate cellular uptake of SPIONs. While qualitative methods are generally based on microscopy techniques, quantitative assays are carried out by techniques such as inductively coupled plasma-mass spectrometry and flow cytometry. However, inexpensive colorimetric methods based on equipments commonly found in chemistry and biochemistry laboratories are preferred for routine measurements. Nevertheless, colorimetric assays must be used judiciously, particularly when nanoparticles are involved, since their interaction with biological constituents tends to lead to quite underestimated results. Thus, herein described is a colorimetric protocol using 2,2'-bipyridine as chromogenic ligand, where each step was optimized and validated by total reflection X-ray fluorescence spectroscopy, realizing a highly reproducible and reliable method for determination of iron content in cells incubated with SPIONs. The limit of blank and limit of detection were determined to be as low as 0.076 and 0.143 µg Fe/mL, using sample volumes as small as 190 µL and a number of cells as low as 2.0 × 105. Furthermore, three different types of surface-functionalized nanoparticles were incorporated in cells and evaluated through this protocol, enabling to monitor the additive effect of o-phosphorylethanolamine (PEA) and folic acid (FA) conjugation on iron oxide nanoparticles (SPION-PEA and SPION-PEA/FA), that enhanced the uptake by HeLa cells, respectively, by four and ten times when compared to SPIONs conjugated with nonbioactive molecules. Graphical abstract Colorimetric determination of superparamagnetic iron oxide nanoparticles (SPIONs) incorporated by cells.

Magnetic Particle Imaging: A Novel in Vivo Imaging Platform for Cancer Detection.

Cancer remains one of the leading causes of death worldwide. Biomedical imaging plays a crucial role in all phases of cancer management. Physicians often need to choose the ideal diagnostic imaging modality for each clinical presentation based on complex trade-offs among spatial resolution, sensitivity, contrast, access, cost, and safety. Magnetic particle imaging (MPI) is an emerging tracer imaging modality that detects superparamagnetic iron oxide (SPIO) nanoparticle tracer with high image contrast (zero tissue background signal), high sensitivity (200 nM Fe) with linear quantitation, and zero signal depth attenuation. MPI is also safe in that it uses safe, in some cases even clinically approved, tracers and no ionizing radiation. The superb contrast, sensitivity, safety, and ability to image anywhere in the body lends MPI great promise for cancer imaging. In this study, we show for the first time the use of MPI for in vivo cancer imaging with systemic tracer administration. Here, long circulating MPI-tailored SPIOs were created and administered intravenously in tumor bearing rats. The tumor was highlighted with tumor-to-background ratio of up to 50. The nanoparticle dynamics in the tumor was also well-appreciated, with initial wash-in on the tumor rim, peak uptake at 6 h, and eventual clearance beyond 48 h. Lastly, we demonstrate the quantitative nature of MPI through compartmental fitting in vivo.

Europium doping of superparamagnetic iron oxide nanoparticles enables their detection by fluorescence microscopy and for quantitative analytics.

BACKGROUND: Pharmacokinetic studies and histological detection of superparamagnetic iron oxide nanoparticles (SPIO) in biomedical research are limited due to a high iron background especially in pathological tissues. OBJECTIVE: The suitability of doping the iron oxide cores of SPIO with europium (Eu) was tested for improved histologic detection and for quantitative analysis without changing their properties as probes for magnetic resonance imaging (MRI). A special variant of SPIO, so called very small superparamagnetic iron oxide nanoparticles (VSOP), was used for this approach. METHODS: VSOP, stabilized by a citrate coating, were synthesized with and without addition of Eu (Eu-VSOP and VSOP, respectively). MR signal enhancing effects of Eu-VSOP and VSOP were studied in vitro. Cellular uptake of Eu-VSOP and VSOP was examined in RAW264.7 cells. For Eu-VSOP, fluorescence microscopy and spectrophotometry were used. Eu fluorescence was enhanced by means of an antenna system. For VSOP, Prussian blue staining and photometry using the phenanthroline method were applied. Results for both VSOP variants were compared. RESULTS: Eu-VSOP and VSOP did not differ with respect to MR signal enhancing effects nor to uptake characteristics in the RAW264.7 cell experiments. Fluorescence microscopy detects Eu-VSOP with higher sensitivity compared to light microscopy using Prussian blue staining. In microscopy as well as in the analytical quantification using fluorescence, detection of Eu-VSOP is not contaminated by Fe background. CONCLUSIONS: Doping the VSOP with Eu allows for their improved detection by fluorescence microscopy and quantitative analysis without changing their cellular uptake characteristics or their MR signal enhancing effects and thus would allow for a multimodal approach for studying their pharmacokinetics and biodistribution in experimental research.

Application of dual 19 F and iron cellular MRI agents to track the infiltration of immune cells to the site of a rejected stem cell transplant.

PURPOSE: Cellular MRI) was used to detect implanted human mesenchymal stem cells (hMSCs) and the resulting macrophage infiltration that occurs in response to xenotransplantation. METHODS: Human mesenchymal stem cells were prelabeled with a fluorine-19 (19 F) agent prior to implantation, allowing for their visualization and quantification over time. Following implantation of 1 × 10619 F-labeled hMSCs into the mouse hind limb, longitudinal imaging was performed to monitor the stem cell graft. Macrophages were labeled in situ by the intravenous administration of an ultrasmall superparamagentic iron oxide (USPIO), allowing for tracking of the inflammatory response. RESULTS: Quantification of 19 F MRI on day 0 agreed with the implanted number of cells, and 19 F signal decreased over time. By day 14, only 22% ± 11% of the original 19 F signal remained. In a second group, USPIO were administered intravenously after implantation of 19 F-labeled hMSCs. When imaged on day 2, a significant decrease in 19 F signal was observed compared to the first group alongside a large signal void region in the corresponding proton images. Immunohistochemistry confirmed the presence of iron-labeled macrophages in the stem cell tract. CONCLUSION: A dual-labeling technique was used to noninvasively track two distinct cell populations simultaneously. This information could be used to provide additional insight into the cause of graft failure. Magn Reson Med 78:713-720, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Quantification and biodistribution of iron oxide nanoparticles in the primary clearance organs of mice using T1 contrast for heating.

PURPOSE: To use contrast based on longitudinal relaxation times (T1 ) or rates (R1 ) to quantify the biodistribution of iron oxide nanoparticles (IONPs), which are of interest for hyperthermia therapy, cell targeting, and drug delivery, within primary clearance organs. METHODS: Mesoporous silica-coated IONPs (msIONPs) were intravenously injected into 15 naïve mice. Imaging and mapping of the longitudinal relaxation rate constant at 24 h or 1 week postinjection were performed with an echoless pulse sequence (SWIFT). Alternating magnetic field heating measurements were also performed on ex vivo tissues. RESULTS: Signal enhancement from positive T1 contrast caused by IONPs was observed and quantified in vivo in liver, spleen, and kidney at concentrations up to 3.2 mg Fe/(g tissue wt.) (61 mM Fe). In most cases, each organ had a linear correlation between the R1 and the tissue iron concentration despite variations in intra-organ distribution, degradation, and IONP surface charge. Linear correlation between R1 and volumetric SAR in hyperthermia therapy was observed. CONCLUSION: The linear dependence between R1 and tissue iron concentration in major organs allows quantitative monitoring of IONP biodistribution in a dosage range relevant to magnetic hyperthermia applications, which falls into the concentration gap between CT and conventional MRI techniques. Magn Reson Med 78:702-712, 2017. © 2016 International Society for Magnetic Resonance in Medicine.