Ultrasmall Paramagnetic Iron Oxide Research Articles

Targeting Peptide, Fluorescent Reagent Modified Magnetic Liposomes Coated with Rapamycin Target Early Atherosclerotic Plaque and Therapy.

Atherosclerosis is the leading cause of global morbidity and mortality. Its therapy requires research in several areas, such as diagnosis of early arteriosclerosis, improvement of the pharmacokinetics and bioavailability of rapamycin as its therapeutic agents. Here, we used the targeting peptide VHPKQHR (VHP) (or fluorescent reagent) to modify the phospholipid molecules to target vascular cell adhesion molecule-1 (VCAM-1) and loaded ultrasmall paramagnetic iron oxide (USPIO/Fe3O4) plus rapamycin (Rap) to Rap/Fe3O4@VHP-Lipo (VHPKQHR-modified magnetic liposomes coated with Rap). This nanoparticle can be used for both the diagnosis and therapy of early atherosclerosis. We designed both an ex vivo system with mouse aortic endothelial cells (MAECs) and an in vivo system with ApoE knockout mice to test the labeling and delivering potential of Rap/Fe3O4@VHP-Lipo with fluorescent microscopy, flow cytometry and MRI. Our results of MRI imaging and fluorescence imaging showed that the T2 relaxation time of the Rap/Fe3O4@VHP-Lipo group was reduced by 2.7 times and 1.5 times, and the fluorescence intensity increased by 3.4 times and 2.5 times, respectively, compared with the normal saline group and the control liposome treatment group. It showed that Rap/Fe3O4@VHP-Lipo realized the diagnosis of early AS. Additionally, our results showed that, compared with the normal saline and control liposomes treatment group, the aortic fluorescence intensity of the Rap/Fe3O4@VHP-Lipo treatment group was significantly weaker, and the T2 relaxation time was prolonged by 8.9 times and 2.0 times, indicating that the targeted diagnostic agent detected the least plaques in the Rap/Fe3O4@VHP-Lipo treatment group. Based on our results, the synthesized theragnostic Rap/Fe3O4@VHP-Lipo serves as a great label for both MRI and fluorescence bimodal imaging of atherosclerosis. It also has therapeutic effects for the early treatment of atherosclerosis, and it has great potential for early diagnosis and can achieve the same level of therapy with a lower dose of Rap.

VHPKQHR Peptide Modified Ultrasmall Paramagnetic Iron Oxide Nanoparticles Targeting Rheumatoid Arthritis for T1-Weighted Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) could be the ideal diagnostic modality for early rheumatoid arthritis (RA). Vascular cell adhesion molecule-1 (VCAM-1) is highly expressed in synovial locations in patients with RA, which could be a potential target protein for RA diagnosis. The peptide VHPKQHR (VHP) has a high affinity to VCAM-1. To make the contrast agent to target RA at an early stage, we used VHP and ultrasmall paramagnetic iron oxide (USPIO) to synthesize UVHP (U stands for USPIO) through a chemical reaction with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide. The size of UVHP was 6.7 nm; the potential was −27.7 mV, and the r 2/r 1 value was 1.73. Cytotoxicity assay exhibited that the cell survival rate was higher than 80% at even high concentrations of UVHP (Fe concentration 200 µg/mL), which showed the UVHP has low toxicity. Compared with no TNF-α stimulation, VCAM-1 expression was increased nearly 3-fold when mouse aortic endothelial cells (MAECs) were stimulated with 50 ng/mL TNF-α; cellular Fe uptake was increased very significantly with increasing UVHP concentration under TNF-α treatment; cellular Fe content was 17 times higher under UVHP with Fe concentration 200 µg/mL treating MAECs. These results indicate that UVHP can target overexpression of VCAM-1 at the cellular level. RA mice models were constructed with adjuvant-induced arthritis. In vivo MRI and biodistribution results show that the signal intensity of knee joints was increased significantly and Fe accumulation in RA model mice compared with normal wild-type mice after injecting UVHP 24 h. These results suggest that we have synthesized a simple, low-cost, and less toxic contrast agent UVHP, which targeted VCAM-1 for early-stage RA diagnosis and generates high contrast in T1-weighted MRI.

Paramagnetic block copolymers: An effective tool for targeted radiography of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis. Accurate diagnosis of RA mostly depends on the quality of magnetic resonance imaging (MRI). To obtain stable and clear imaging signals, it is necessary to design and develop a superstable and highly sensitive contrast agent. This study synthesized a diblock polymer polyethylene glycol–tert-butyl polyacrylate (PEG-b-PAA) by in situ polyol polymerization, coated it with ultrasmall paramagnetic iron oxide (USPIO), and conjugated folic acid to the PEG-b-PAA/USPIO surface to impart targeting function. The addition of USPIO effectively enhanced MRI quality in delayed T2-weighted images (T2WI), as observed through synovial signal changes other than morphological changes, early monitoring RA lesions, and drug treatment response. Enhanced T2WI helped evaluate the characteristics of synovial perfusion, which further confirmed the feasibility of MRI using FA-PEG-b-PAA/USPIO. These results showed that FA-PEG-b-PAA/USPIO has great potential in the clinical application of MRI for RA diagnosis.

Evaluation of scaffold microstructure and comparison of cell seeding methods using micro-computed tomography-based tools.

Micro-computed tomography (micro-CT) provides a means to analyse and model three-dimensional (3D) tissue engineering scaffolds. This study proposes a set of micro-CT-based tools firstly for evaluating the microstructure of scaffolds and secondly for comparing different cell seeding methods. The pore size, porosity and pore interconnectivity of supercritical CO2 processed poly(l-lactide-co-ɛ-caprolactone) (PLCL) and PLCL/β-tricalcium phosphate scaffolds were analysed using computational micro-CT models. The models were supplemented with an experimental method, where iron-labelled microspheres were seeded into the scaffolds and micro-CT imaged to assess their infiltration into the scaffolds. After examining the scaffold architecture, human adipose-derived stem cells (hASCs) were seeded into the scaffolds using five different cell seeding methods. Cell viability, number and 3D distribution were evaluated. The distribution of the cells was analysed using micro-CT by labelling the hASCs with ultrasmall paramagnetic iron oxide nanoparticles. Among the tested seeding methods, a forced fluid flow-based technique resulted in an enhanced cell infiltration throughout the scaffolds compared with static seeding. The current study provides an excellent set of tools for the development of scaffolds and for the design of 3D cell culture experiments.

Yolk-shell nanovesicles endow glutathione-responsive concurrent drug release and T1 MRI activation for cancer theranostics

The effort of incorporating therapeutic drugs with imaging agents has been one of the mainstreams of nanomedicine, which holds great promise in cancer treatment in terms of monitoring therapeutic drug activity and evaluating prognostic index. However, it is still technically challenging to develop nanomedicine endowing a spatiotemporally controllable mechanism of drug release and activatable imaging capability. Here, we developed a yolk-shell type of GSH-responsive nanovesicles (NVs) in which therapeutic drug (Doxorubicin, DOX) and magnetic resonance imaging (MRI) contrast agent (ultrasmall paramagnetic iron oxide nanoparticles, USPIO NPs) formed complexes (denoted as USD) and were encapsulated inside the NVs. The formation of USD complexes is mediated by both the electrostatic adsorption between DOX and poly(acrylic acid) (PAA) polymers and the DOX-iron coordination effect on USPIO NPs. The obtained USD NVs showed a unique yolk-shell structure with restrained drug activity and quenched T1 MRI contrast ability which, on the other hand, can respond to glutathione (GSH) and lead to drug release and T1 contrast activation in a spatiotemporally concurrent manner. Furthermore, the USD NVs exhibited great potential to kill HCT116 cancer cells in vitro and effectively inhibit the tumor growth in vivo. This study may shed light on the design of sophisticated nanotheranostics in precision nanomedicine.

In Vivo MRI Tracking of Mesenchymal Stromal Cells Labeled with Ultrasmall Paramagnetic Iron Oxide Particles after Intramyocardial Transplantation in Patients with Chronic Ischemic Heart Disease.

Background While regenerative stem cell therapy for ischemic heart disease has moved into phase 3 studies, little is still known about retention and migration of cell posttransplantation. In human studies, the ability to track transplanted cells has been limited to labeling with radioisotopes and tracking using nuclear imaging. This method is limited by low resolution and short half-lives of available radioisotopes. Longitudinal tracking using magnetic resonance imaging (MRI) of myocardial injected cells labeled with iron oxide nanoparticles has shown promising results in numerous preclinical studies but has yet to be evaluated in human studies. We aimed to evaluate MRI tracking of mesenchymal stromal cells (MSCs) labeled with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles after intramyocardial transplantation in patients with ischemic heart disease (IHD). Methods Five no-option patients with chronic symptomatic IHD underwent NOGA-guided intramyocardial transplantation of USPIO-labeled MSCs. Serial MRI scans were performed to track labeled cells both visually and using semiautomated T2∗ relaxation time analysis. For safety, we followed symptoms, quality of life, and myocardial function for 6 months. Results USPIO-labeled MSCs were tracked for up to 14 days after transplantation at injection sites both visually and using semiautomated regional T2∗ relaxation time analysis. Labeling of MSCs did not impair long-term safety of treatment. Conclusion This was a first-in-man clinical experience aimed at evaluating the utility of MRI tracking of USPIO-labeled bone marrow-derived autologous MSCs after intramyocardial injection in patients with chronic IHD. The treatment was safe, and cells were detectable at injection sites up to 14 days after transplantation. Further studies are needed to clarify if MSCs migrate out of the injection area into other areas of the myocardium or if injected cells are washed out into the peripheral circulation. The trial is registered with ClinicalTrials.gov NCT03651791.

Preparation and characterization of 3D porous conductive scaffolds with magnetic resonance enhancement in tissue engineering

Magnetic resonance imaging (MRI), as a diagnostic tool in tissue engineering, has received widespread attention because of its ability to consistently provide degradation and absorption of implants in vivo. For some specific human tissues and organs, such as nerves, muscles and myocardium, their regeneration requires tissue engineering scaffolds have a good electrical conductivity. Graphene oxide (GO) has been extensively studied as a conductive biomaterial having mechanical reinforcement. Based on the above, we propose an MRI conductive scaffold containing gelatin (Gel)/gelatin-polycaprolactone (Gel-PCL)/ultra-small paramagnetic iron oxide (USPIO)/graphene oxide (GO) (Gel/Gel-PCL/USPIO/GO). Their physical and chemical properties as well as biocompatibility are measured in vitro. The purpose of doping USPIO was developed for non-invasive monitoring of tissue engineered implants and tissue reconstruction. Functional modification of GO to match electrophysiological requirement. Co-culture with bone marrow mesenchymal stem cells showed good biocompatibility. Blood experiments have also demonstrated the feasibility of scaffolds as tissue engineered implants. The USPIO-labeled conductive scaffold, as an effective image-guided and electrically stimulating implant, appears to be a reconstruction platform for specific tissues and organs.

Imaging of distant metastases of prostate cancer.

The detection of distant metastases at the initial diagnosis of prostate cancer (PCa) establishes the treatment approach and has a prognostic value, nevertheless it is not well established. Since proposed staging approaches often contradict each other, we aimed to compare the current imaging techniques for staging of advanced PCa, including future applications of the most innovative methods. Conventional imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) have been employed for metastatic staging (both N and M staging) of men with high-risk PCa, but surgical pelvic dissection remains the gold standard for N staging. However, functional MRI by using diffusion-weighted imaging, MR lymphography (MRL) with ultra-small paramagnetic iron oxide particles (USPIO), and hybrid PET/MRI imaging showed both high sensitivity and high specificity for nodal staging and depicting metastases. The standard of practice for M staging in PCa includes the radionuclide bone scan and targeted X-ray film, but their performance has generally been poor. Recently, MRI showed promising results with applications in both local and distant staging. Finally, with the development of new PET tracers, PET/CT and PET/MRI offer a combination of excellent pharmacokinetic characteristics, functional information, and precise anatomic localization and morphological correlation of tumor lesions.

Ultrasmall Paramagnetic Iron Oxide Nanoprobe Targeting Epidermal Growth Factor Receptor for In Vivo Magnetic Resonance Imaging of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common worldwide cancer that is rising rapidly in incidence. MRI is a powerful noninvasive imaging modality for HCC detection, but lack of specific contrast agents limits visualization of small tumors. EGFR is frequently overexpressed in HCC and is a promising target. Peptides have fast binding kinetics, short circulatory half-life, low imaging background, high vascular permeability, and enhanced tissue diffusion for deep tumor penetration. We demonstrate a peptide specific for EGFR labeled with an ultrasmall paramagnetic iron oxide (UPIO) nanoparticle with 3.5 nm dimensions to target HCC using T1-weighted MRI. We modified the hydrophobic core with oleic acid and capped with PEGylated phospholipids DSPE-PEG and DSPE-PEG-Mal. The EGFR peptide is attached via thioether-mediated conjugation of a GGGSC linker to the maleimide-terminated phospholipids. On in vivo MR images of HCC xenograft tumors, we observed peak nanoprobe uptake at 2 h post-injection followed by a rapid return to baseline by ∼24 h. We measured significantly greater MR signal in tumor with the targeted nanoprobe versus scrambled peptide, blocked peptide, and Gadoteridol. Segmented regions on MR images support rapid renal clearance. No significant difference in animal weight, necropsy, hematology, and chemistry was found between treatment and control groups at one month post-injection. Our nanoprobe based on an EGFR specific peptide labeled with UPIO designed for high stability and biocompatibility showed rapid tumor uptake and systemic clearance to demonstrate safety and promise for clinical translation to detect early HCC.

USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood-induced arthritis: a pilot study.

Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 μmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post-USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation.

Leakage and water exchange characterization of gadofosveset in the myocardium

PurposeTo determine the compartmentalization of the blood pool agent gadofosveset and the effect of its transient binding to albumin on the quantification of steady-state fractional myocardial blood volume (fMBV). MethodsMyocardial vascular fraction measurements were simulated assuming the limiting cases (slow or fast) of two-compartment water exchange for different contrast agent injection concentrations, binding fractions, bound and free relaxivities, and true cardiac vascular fractions.fMBV was measured in five healthy volunteers (4 males, 1 female, average age 33) at 1.5T after administration of five injections of gadofosveset. The measurements in the volunteers were retrospectively compared to measurements of fMBV after three serial injections of the ultra-small, paramagnetic iron oxide (USPIO) blood pool agent ferumoxytol in an experimental animal. The true fMBV and exchange rate of water protons in both human and animal data sets was determined by chi square minimization. ResultsSimulations showed an error in the measurement of fMBV due to partial binding of gadofosveset of less than 30%. Measured fMBV values over-estimate simulation predictions, and approach cardiac extracellular volume (22%), which suggests that the intravascular assumption may not be appropriate for the myocardium, although it may apply to more distal perfusion beds. In comparison, fMBV measured with ferumoxytol (5%, with slow water proton exchange across vascular wall) agree with published values of myocardial vascular fraction. Further comparison between myocardium relaxation rates induced by gadofosveset and by other extracellular and intravascular contrast agents showed that gadofosveset behaves like an extracellular contrast agent. ConclusionsThe distribution of the volunteer data indicates that a three-compartment model, with slow water exchange of gadofosveset and water protons between the vascular and interstitial compartments, and fast water exchange between the interstitium and the myocytes, is appropriate. The ferumoxytol measurements indicate that this USPIO is an intravascular contrast agent that can be used to quantify myocardial blood volume, with the appropriate correction for water exchange using a two-compartment water exchange model.

Highlights of This Issue

The impact of pretransplantation iron overload on patient outcome after allogeneic stem cell transplantation is controversially discussed, because recent studies were retrospective in nature and relied on interference prone surrogate markers. Wermke and colleagues report prospective data based on liver MRI to quantify the extent of body iron in this context. In their cohort, surrogate parameters failed to accurately identify iron overloaded patients. Moreover, only liver iron as determined by MRI but not serum ferritin or transfusion burden predicted for survival. It will be important to understand the mechanisms by which excessive iron contributes to a worse outcome after transplantation.Measurement of HER family signaling is critically important in the clinical management of a significant number of breast cancer patients. Using a highly sensitive protein array, Wulfkuhle and colleagues identified a new subgroup of breast cancer patients with HER2 pathway activation in an otherwise HER2- negative cohort. These patients are not identified by current clinically approved or genomic tests for HER2, and are thus excluded from anti-HER2 therapies. Protein pathway activation mapping of receptor tyrosine kinases and linked signaling pathways may identify new patient cohorts that could benefit from existing FDA cleared and/or experimental molecular targeted inhibitors, if these measurements prove clinically useful.The novel magnetic resonance imaging method of vessel size imaging (VSI) provides in vivo images of blood volume and mean vessel radius. Using an intravascular contrast agent of the ultrasmall paramagnetic iron oxide class, Nielsen and colleagues utilized VSI for investigating the effect of the vascular disrupting agent combretastatin in a murine tumor model. Treatment with combretastatin reduced blood volume and indicated a change in the distribution of vessel sizes. VSI may be valuable in assessing tumor angiogenesis, prediction of response to vascular disrupting agents, and treatment monitoring.Adjuvant setting represents the optimal set to test the tumor vaccines because of the more conserved immune conditions of early cancer patients. In this phase II randomized trial, Filipazzi and colleagues used modified tumor peptides to immunize stage II–III melanoma patients. However, in spite of a prompt and persisting immune response, no evident clinical benefit was detected in vaccinated versus control patients. The limited number of true antitumor T cells induced by vaccination, unraveled by an extensive immunologic monitoring, shows that the choice of the immunization strategy is a critical step and that the use of modified peptides should be reconsidered.

Role of magnetic resonance imaging in bladder cancer: current status and emerging techniques

To evaluate the current status of magnetic resonance imaging (MR) as a staging tool for bladder cancer. To investigate the role of MR in assessing chemotherapeutic response in bladder cancer patients. A Pubmed/MEDLINE search was conducted to identify original articles, review articles, and editorials regarding the use of MR in bladder cancer. Contrast-enhanced MR and diffusion weighted MR (DW-MRI) can likely distinguish between non-muscle invasive bladder cancer and muscle invasive cancer with >80% accuracy. Some advantages of DW-MRI are the differentiation of benign versus malignant tissue involvement without the need for intravenous contrast, and the possibility of obtaining information on histologic grade and T stage. Traditional MR sequence have low sensitivity for identifying small lymph node metastases but MR lymphography (MRL) using ultra-small paramagnetic iron oxide (USPIO) may enhance their detectin. There may be a role for DW-MRI in the evaluation of chemotherapeutic response in bladder cancer patients. To date, sample sizes and study designs are insufficient to clearly establish the role of MR in bladder cancer management, and to this end, well designed prospective trials are needed.

Molecular Imaging of Brain Lipid Environment of Lymphocytes in Amyotrophic Lateral Sclerosis Using Magnetic Resonance Imaging and SECARS Microscopy

This paper highlights some of the key technologies of using two innovative molecular imaging modalites, magnetic resonance imaging (MRI) and nonlinear optical microscopy, for imaging intravenously injected ultra small paramagnetic iron oxide nanoparticles cross linked with antibodies (CLUSPIO) in the amyotrophic lateral sclerosis (ALS) experimental model in vivo or ex vivo, respectively. Intensive efforts have been made in investigating the causes of abnormalities in lipid metabolism, monitored in some neurodegenerative disorders systems. It has been shown that an abnormal accumulation of some common lipids in motor nerve cells may play a critical role in the development of amyotrophic lateral sclerosis. The presented experiments were performed on brain specimens from the transgenic rat model expressing multiple copies of mutated (G93A) human SOD-1 gene, after CD4+ lymphocytes were magnetically labeled with i.v.i. CLUSPIO antibodies. In vivo MRI revealed marked signal intensity enhancements in specific pathological regions of the ALS rat brain as compared to the wild type. Surface-enhanced coherent anti-Stokes Raman scattering (SECARS) microscopy indicated cellular interactions based on lipids association to anti-CD4 CLUSPIO.

Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model

MRI was employed to follow the neurodegenerative foci and the localization of inflammatory cells by magnetically labeled CD4+ or CD8+ lymphocytes in the ischemia/reperfusion long-lived rats (9 and 13 months after 10 min of cardiac arrest). MRI of ischemic rats showed: (1) blood-brain barrier (BBB) leakage in the area of the dorsal hippocampus and brainstem-hindbrain level in basal cerebellum, (2) unlike anti-CD8 magnetic antibodies anti-CD4 ultra small paramagnetic iron oxide particles (USPIO) antibodies revealed hypointense areas in the brainstem-interbrain region and caudoputamen not found in animals that were not injected with USPIO antibodies, and (3) dilation in the retrosplenial area. Immunocytochemistry revealed microglial activation in the hippocampus and striatum, with indications of activation in thalamic lateral dorsal nuclei and the subventricular zone. In the CA1 and CA3 regions, it was noted that OX42- and ED1-positive granules appear in neuronal somata. Immunostaining of lymphocytes with TCR confirmed the T-cell presence in ischemic brain parenchyma of the hippocampus and striatum. The above observations thus point to a persistent dysfunction of BBB that in long-term may still lead to infiltration of T cells that are predominantly of helper (CD4+) type. Such inflammatory processes are backed by microglial activity even up to 1 year after ischemia/reperfusion. Moreover, in these animals an augmented expression of neurogenesis markers and neuroblast migration was also revealed in the subventricular zone. Thus, a balance of degenerative processes and inflammatory surveillance with neurogenesis could determine the long-term outcome of global ischemia survival or the previously proposed formation of amyloid plaques and Alzheimer's-type dementia.

Imaging cellular markers of neuroinflammation in the brain of the rat model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder affecting upper and lower motoneurons. Since immune disbalance is known to be an important manifestation of the disease, working with the familial ALS rat model, hSODG93A (containing multiple copies of the human SOD1 G93A mutation), we were particularly interested in following by live magnetic resonance imaging (MRI) the immune cells labeled by ultra small paramagnetic iron oxide (USPIO) nanoparticles. In addition, microglial activation was studied by immunocytochemistry. MRI of USPIO labeled Tcells revealed CD4+ lymphocyte infiltration in the midbraininterbrain region while the CD8+ cells were more confined to the brainstem region. By way of gadolinium (Gd) contrast it was also confirmed that the bloodbrain barrier (BBB) was compromised. Moreover, it was revealed that the regions of BBB breakthrough were congruent with the MRI foci of Tcell infiltration. Immunocytochemistry revealed microglial activation and fusion, possibly phagocytic interactions with neurons in the hippocampus and brainstem. These observations prove the existence of an elaborate inflammatory process in the brain of hSODG93A rats, and also demonstrates the complexity and multifocality of ALS as having its inflammatory manifestations also in the central nervous system (hippocampus) distinct from clinically described motor foci of degeneration.

First Multimodal Embolization Particles Visible on X-ray/Computed Tomography and Magnetic Resonance Imaging

Embolization therapy is gaining importance in the treatment of malignant lesions, and even more in benign lesions. Current embolization materials are not visible in imaging modalities. However, it is assumed that directly visible embolization material may provide several advantages over current embolization agents, ranging from particle shunt and reflux prevention to improved therapy control and follow-up assessment. X-ray- as well as magnetic resonance imaging (MRI)-visible embolization materials have been demonstrated in experiments. In this study, we present an embolization material with the property of being visible in more than one imaging modality, namely MRI and x-ray/computed tomography (CT). Characterization and testing of the substance in animal models was performed. To reduce the chance of adverse reactions and to facilitate clinical approval, materials have been applied that are similar to those that are approved and being used on a routine basis in diagnostic imaging. Therefore, x-ray-visible Iodine was combined with MRI-visible Iron (Fe3O4) in a macroparticle (diameter, 40-200 μm). Its core, consisting of a copolymerized monomer MAOETIB (2-methacryloyloxyethyl [2,3,5-triiodobenzoate]), was coated with ultra-small paramagnetic iron oxide nanoparticles (150 nm). After in vitro testing, including signal to noise measurements in CT and MRI (n = 5), its ability to embolize tissue was tested in an established tumor embolization model in rabbits (n = 6). Digital subtraction angiography (DSA) (Integris, Philips), CT (Definition, Siemens Healthcare Section, Forchheim, Germany), and MRI (3 Tesla Magnetom Tim Trio MRI, Siemens Healthcare Section, Forchheim, Germany) were performed before, during, and after embolization. Imaging signal changes that could be attributed to embolization particles were assessed by visual inspection and rated on an ordinal scale by 3 radiologists, from 1 to 3. Histologic analysis of organs was performed. Particles provided a sufficient image contrast on DSA, CT (signal to noise [SNR], 13 ± 2.5), and MRI (SNR, 35 ± 1) in in vitro scans. Successful embolization of renal tissue was confirmed by catheter angiography, revealing at least partial perfusion stop in all kidneys. Signal changes that were attributed to particles residing within the kidney were found in all cases in all the 3 imaging modalities. Localization distribution of particles corresponded well in all imaging modalities. Dynamic imaging during embolization provided real-time monitoring of the inflow of embolization particles within DSA, CT, and MRI. Histologic visualization of the residing particles as well as associated thrombosis in renal arteries could be performed. Visual assessment of the likelihood of embolization particle presence received full rating scores (153/153) after embolization. Multimodal-visible embolization particles have been developed, characterized, and tested in vivo in an animal model. Their implementation in clinical radiology may provide optimization of embolization procedures with regard to prevention of particle misplacement and direct intraprocedural visualization, at the same time improving follow-up examinations by utilizing the complementary characteristics of CT and MRI. Radiation dose savings can also be considered. All these advantages could contribute to future refinements and improvements in embolization therapy. Additionally, new approaches in embolization research may open up.

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density (Q). Here, this technique is validated with direct comparisons to ex vivo micro-computed tomography angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and Q by two antiangiogenic therapeutics [anti-vascular endothelial growth factor (anti-VEGF) and anti-neuropilin-1] on an HM7 colorectal tumor model. Anti-vascular endothelial growth factor reduced blood volume by 36±3% (p<0.0001) and Q by 52±3% (p<0.0001) at 48 h post-treatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18±6% (p<0.05) and a reduction in Q of 33±5% (p<0.05) at 48 h post-treatment.

In vivo targeted molecular imaging for activated platelets by mri using USPIO-fucoidan in rat abdominal aortic aneuryms model

Background P-selectin, expressed on the activated platelets and endothelial cells, is one of the key adhesion molecules that regulate leukocyte trafficking in atherosclerosis. The natural and canonical ligand of selectins is a specific tetrasaccharide structure known as 6-sulfo sialyl Lewis X (SLeX). Fucoidans refer to a type of polysaccharide that contains L-fucose and sulfate ester groups, mainly derived from brown seaweed, and binds strongly to P-selectin. We assessed the hypothesis that a new MRI contrast agent made of fucoidan conjugated with ultra small paramagnetic iron oxide (USPIO) can demonstrate the presence of activated platelets in thrombus of an expanding aneurysm.

Molecular imaging of tumor angiogenesis using RGD-labeled iron oxide nanoparticles

Integrin is often significantly upregulated in activated endothelial cells during tumor angiogenesis. The arginine-glycine-aspartic acid (RGD) peptide sequence is a specific recognition motif to αvβ3 integrin. In this study, a RGD labeled, Poly lactic acid (PLA) coated ultrasmall paramagnetic iron oxide (USPIO) (referred to as RGD-PLA-USPIO) were developed and the ability to detect tumor angiogenesis was investigated in vitro and in vivo. Increased uptake of RGD-PLA-USPIO by human umbilical vein endothelial cells (HUVECs) was detected by Prussian blue stain and transmission electronic microscopy (TEM). Pronounced signal decrease in T2*-weighted magnetic resonance image (MRI) and heterogeneous arrangement of neovasculature of tumor tissue were clearly identified in Vx-2 tumor model. The MR signal of contralateral muscle only could be seen a slight background change after either RGD-PLA-USPIO or PLA-USPIO injection. These studies demonstrate the efficiency of RGD-PLA-USPIO to visualize αvβ3 integrin in activated tumor endothelial cells and its potential for detecting and monitoring tumor vasculature change after therapy