AC Magnetic Susceptibility: Mathematical Modeling and Experimental Realization on Poly-Crystalline and Single-Crystalline High-Tc Superconductors YBa2Cu3O7-δ and Bi2-xPbxSr2Ca2Cu3O10+y.

The multifaceted inductive technique of AC magnetic susceptibility (ACMS) provides versatile and reliable means for the investigation of the respective properties of magnetic and superconducting materials. Here, we explore, both mathematically and experimentally, the ACMS set-up, based on four coaxial pick-up coils assembled in the second-derivative configuration, when employed in the investigation of differently shaped superconducting specimens of poly-crystalline YBa2Cu3O7-δ and Bi2-xPbxSr2Ca2Cu3O10+y and single-crystalline YBa2Cu3O7-δ. Through the mathematical modeling of both the ACMS set-up and of linearly responding superconducting specimens, we obtain a closed-form relation for the DC voltage output signal. The latter is translated directly to the so-called extrinsic ACMS of the studied specimen. By taking into account the specific characteristics of the studied high-Tc specimens (such as the shape and dimensions for the demagnetizing effect, porosity for the estimation of the superconducting volume fraction, etc.), we eventually draw the truly intrinsic ACMS of the parent material. Importantly, this is carried out without the need for any calibration specimen. The comparison of the mathematical modeling with the experimental data of the aforementioned superconducting specimens evidences fair agreement.

Gamma-Camera Direct Imaging of the Plasma and On/Intra Cellular Distribution of the 99mTc-DPD-Fe3O4 Dual-Modality Contrast Agent in Peripheral Human Blood.

The radiolabeled iron oxide nanoparticles constitute an attractive choice to be used as dual-modality contrast agents (DMCAs) in nuclear medical diagnosis, due to their ability to combine the benefits of two imaging modalities, for instance single photon emission computed tomography (SPECT) with magnetic resonance imaging (MRI). Before the use of any DMCA, the investigation of its plasma extra- and on/intra cellular distribution in peripheral human blood is of paramount importance. Here, we focus on the in vitro investigation of the distribution of 99mTc-DPD-Fe3O4 DMCA in donated peripheral human blood (the ligand 2-3-dicarboxypropane-1-1-diphosphonic-acid is denoted as DPD). Initially, we described the experimental methods we performed for the radiosynthesis of the 99mTc-DPD-Fe3O4, the preparation of whole blood and blood plasma samples, and their incubation conditions with 99mTc-DPD-Fe3O4. More importantly, we employed a gamma-camera apparatus for the direct imaging of the 99mTc-DPD-Fe3O4-loaded whole blood and blood plasma samples when subjected to specialized centrifugation protocols. The direct comparison of the gamma-camera data obtained at the exact same samples before and after their centrifugation enabled us to clearly identify the distribution of the 99mTc-DPD-Fe3O4 in the two components, plasma and cells, of peripheral human blood.

Radiolabeled Iron Oxide Nanoparticles as Dual Modality Contrast Agents in SPECT/MRI and PET/MRI.

During the last decades, the utilization of imaging modalities such as single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI) in every day clinical practice has enabled clinicians to diagnose diseases accurately at early stages. Radiolabeled iron oxide nanoparticles (RIONs) combine their intrinsic magnetic behavior with the extrinsic character of the radionuclide additive, so that they constitute a platform of multifaceted physical properties. Thus, at a practical level, RIONs serve as the physical parent of the so-called dual-modality contrast agents (DMCAs) utilized in SPECT/MRI and PET/MRI applications due to their ability to combine, at real time, the high sensitivity of SPECT or PET together with the high spatial resolution of MRI. This review focuses on the synthesis and in vivo investigation of both biodistribution and imaging efficacy of RIONs as potential SPECT/MRI or PET/MRI DMCAs.

99mTc-Labeled Iron Oxide Nanoparticles as Dual-Modality Contrast Agent: A Preliminary Study from Synthesis to Magnetic Resonance and Gamma-Camera Imaging in Mice Models.

The combination of two imaging modalities in a single agent has received increasing attention during the last few years, since its synergistic action guarantees both accurate and timely diagnosis. For this reason, dual-modality contrast agents (DMCAs), such as radiolabeled iron oxide (namely Fe3O4) nanoparticles, constitute a powerful tool in diagnostic applications. In this respect, here we focus on the synthesis of a potential single photon emission computed tomography/magnetic resonance imaging (SPECT/MRI) DMCA, which consists of Fe3O4 nanoparticles, surface functionalized with 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD) and radiolabeled with 99mTc, [99mTc]Tc-DPD-Fe3O4. The in vitro stability results showed that this DMCA is highly stable after 24 h of incubation in phosphate buffer saline (~92.3% intact), while it is adequately stable after 24 h of incubation with human serum (~67.3% intact). Subsequently, [99mTc]Tc-DPD-Fe3O4 DMCA was evaluated in vivo in mice models through standard biodistribution studies, MR imaging and gamma-camera imaging. All techniques provided consistent results, clearly evidencing noticeable liver uptake. Our work documents that [99mTc]Tc-DPD-Fe3O4 has all the necessary characteristics to be a potential DMCA.

Immunocompatibility of a new dual modality contrast agent based on radiolabeled iron-oxide nanoparticles.

Radiolabeled magnetic nanoparticles are promising candidates as dual-modality-contrast-agents (DMCA) for diagnostic applications. The immunocompatibility of a new DMCA is a prerequisite for subsequent in vivo applications. Here, a new DMCA, namely Fe3O4 nanoparticles radiolabeled with 68Ga, is subjected to immunocompatibility tests both in vitro and in vivo. The in vitro immunocompatibility of the DMCA relied on incubation with donated human WBCs and PLTs (five healthy individuals). Optical microscopy (OM) and atomic force microscopy (AFM) were employed for the investigation of the morphological characteristics of WBCs and PLTs. A standard hematology analyzer (HA) provided information on complete blood count. The in vivo immunocompatibility of the DMCA was assessed through its biodistribution among the basic organs of the mononuclear phagocyte system in normal and immunodeficient mice (nine in each group). In addition, Magnetic Resonance Imaging (MRI) data were acquired in normal mice (three). The combined OM, AFM and HA in vitro data showed that although the DMCA promoted noticeable activation of WBCs and PLTs, neither degradation nor clustering were observed. The in vivo data showed no difference of the DMCA biodistribution between the normal and immunodeficient mice, while the MRI data prove the efficacy of the particular DMCA when compared to the non-radiolabeled, parent CA. The combined in vitro and in vivo data prove that the particular DMCA is a promising candidate for future in vivo applications.

Hemocompatibility of gallium-68 labeled iron oxide nanoparticles coated with 2,3-dicarboxypropane-1,1-diphosphonic acid.

Dual-modality contrast agents (DMCA), such as radiolabeled magnetic nanoparticles, have attracted significant attention in diagnostic applications due to their potency for the timely and accurate diagnosis of diseases. The hemocompatibility of a candidate DMCA with human blood is essential for the investigation of its application in vivo. In this respect, here we focused on the evaluation of the hemocompatibility of a new DMCA, that is based on iron oxide nanoparticles (i.e. Fe3O4 magnetite), with human red blood cells (RBCs). The specific iron oxide nanoparticles are surface functionalized with 2,3-dicarboxypropane-1,1-diphosphonic acid (-DPD) and radiolabeled with gallium-68 (68Ga), resulting in 68Ga-DPD-Fe3O4. RBCs of five healthy individuals are incubated at room temperature for 120 min without and with 68Ga-DPD-Fe3O4 at concentrations 0.1 and 1.0 mg/ml. Optical microscopy (OM) and atomic force microscopy (AFM) are employed to assess detailed information on the overall morphological and geometrical characteristics of the entire cell at the microscopic (10-6 m) level and on the membrane morphology at the nanoscopic (10-9 m) level. In addition, a standard hematology analyzer (HA) is used to obtain complete blood count information. At the microscopic level, the combined OM, AFM and HA data revealed that the overall shape/size characteristics of RBCs were preserved upon incubation with 68Ga-DPD-Fe3O4. However, at the nanoscopic level, the AFM results revealed two different kinds of local deconstructions of the RBCs membrane, termed holes and ulcer-like abnormalities, that were observed in both the DMCA-free and DMCA-incubated samples. Holes did not exhibit any statistically significant difference upon incubation with the 68Ga-DPD-Fe3O4 DMCA. On the contrary, ulcer-like abnormalities exhibited two statistically significant differences upon incubation with the 68Ga-DPD-Fe3O4 DMCA. First, increased percentage of RBCs having at least one ulcer-like abnormality; in DMCA-incubated samples 78.6 ± 11.6% for CDMCA = 0.1 mg/ml and 80.4 ± 11.1% for CDMCA = 1.0 mg/ml, while in DMCA-free samples 61.2 ± 8.4% prior to and 63.6 ± 13.5% after incubation. Second, increased number of ulcer-like abnormalities per RBC; in DMCA-incubated samples 4.26 ± 0.62 for CDMCA = 0.1 mg/ml and 3.99 ± 0.97 for CDMCA = 1.0 mg/ml, while in DMCA-free samples 2.84 ± 0.54 prior to and 2.98 ± 0.50 after incubation. The combined OM, AFM and HA results prove fair hemocompatibility of the 68Ga-DPD-Fe3O4 DMCA with human RBCs, thus documenting its potential use in imaging applications.

A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis.

Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99mTc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe3O4-DMSA-SMCC-BCZM-99mTc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe3O4-DMSA-SMCC-BCZM-99mTc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe3O4-DMSA-SMCC-BCZM-99mTc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe3O4-DMSA-SMCC-BCZM-99mTc for targeted dual-modality imaging. Our findings indicate that Fe3O4-DMSA-SMCC-BCZM-99mTc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.

Gallium-68 Labeled Iron Oxide Nanoparticles Coated with 2,3-Dicarboxypropane-1,1-diphosphonic Acid as a Potential PET/MR Imaging Agent: A Proof-of-Concept Study.

The aim of this study was to develop a dual-modality PET/MR imaging probe by radiolabeling iron oxide magnetic nanoparticles (IONPs), surface functionalized with water soluble stabilizer 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), with the positron emitter Gallium-68. Magnetite nanoparticles (Fe3O4 MNPs) were synthesized via coprecipitation method and were stabilized with DPD. The Fe3O4-DPD MNPs were characterized based on their structure, morphology, size, surface charge, and magnetic properties. In vitro cytotoxicity studies showed reduced toxicity in normal cells, compared to cancer cells. Fe3O4-DPD MNPs were successfully labeled with Gallium-68 at high radiochemical purity (>91%) and their stability in human serum and in PBS was demonstrated, along with their further characterization on size and magnetic properties. The ex vivo biodistribution studies in normal Swiss mice showed high uptake in the liver followed by spleen. The acquired PET images were in accordance with the ex vivo biodistribution results. Our findings indicate that 68Ga-Fe3O4-DPD MNPs could serve as an important diagnostic tool for biomedical imaging.

Does the extracorporeal circulation worsen anemia in hemodialysis patients? Investigation with advanced microscopes of red blood cells drawn at the beginning and end of dialysis.

BACKGROUND: In hemodialysis (HD) patients, anemia relates to three main factors: insufficient production of erythropoietin; impaired management of iron; and decreased lifespan of red blood cells (RBCs). The third factor can relate to structural deterioration of RBCs due to extrinsic (extracorporeal circuit; biochemical activation and/or mechanical stress during dialysis) and intrinsic (uremic milieu; biochemical interference of the RBC membrane constituents with toxins) mechanisms. Herein, we evaluate information accessed with advanced imaging techniques at the cellular level. METHODS: Atomic force and scanning electron microscopes were employed to survey intact RBCs (iRBCs) of seven HD patients in comparison to seven healthy donors. The extrinsic factor was investigated by contrasting pre- and post-HD samples. The intrinsic environment was investigated by comparing the microscopy data with the clinical ones. RESULTS: The iRBC membranes of the enrolled HD patients were overpopulated with orifice-like (high incidence; typical size within 100-1,000 nm) and crevice-like (low incidence; typical size within 500-4,000 nm) defects that exhibited a statistically significant (P < 0.05) relative increase (+55% and +350%, respectively) in respect to healthy donors. The relative variation of the orifice and crevice indices (mean population of orifices and crevices per top membrane surface) between pre- and post-HD was not statistically significant (-3.3% and +4.5%, respectively). The orifice index correlates with the concentrations of urea, calcium, and phosphorus, but not, however, with that of creatinine. CONCLUSION: Extracorporeal circulation is not detrimental to the structural integrity of RBC membranes. Uremic milieu is a candidate cause of RBC membrane deterioration, which possibly worsens anemia.

Radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI agents.

Dual-modality contrast agents, such as radiolabeled nanoparticles, are promising candidates for a number of diagnostic applications, since they combine the advantages of two different imaging modalities, namely SPECT or PET imaging with MR imaging. The benefit of such a combination is to more accurately interpret disease and abnormalities in vivo, by exploiting the advantages of each imaging technique, i.e. high sensitivity for SPECT/PET, high resolution anatomical information for MRI. In this review article, we provide an overview of recent findings in the synthesis, evaluation and application of radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI imaging probes.

Rapid magnetic heating treatment by highly charged maghemite nanoparticles on Wistar rats exocranial glioma tumors at microliter volume.

One of the most significant challenges implementing colloidal magnetic nanoparticles in medicine is the efficient heating of microliter quantities by applying a low frequency alternating magnetic field. The ultimate goal is to accomplish nonsurgically the treatment of millimeter size tumors. Here, we demonstrate the synthesis, characterization, and the in vitro as well as in vivo efficiency of a dextran coated maghemite (gamma-Fe(2)O(3)) ferrofluid with an exceptional response to magnetic heating. The difference to previous synthetic attempts is the high charge of the dextran coating, which according to our study maintains the colloidal stability and good dispersion of the ferrofluid during the magnetic heating stage. Specifically, in vitro 2 mul of the ferrofluid gives an outstanding temperature rise of 33 degrees C within 10 min, while in vivo treatment, by infusing 150 mul of the ferrofluid in animal model (rat) glioma tumors, causes an impressive cancer tissue dissolution.

Surveying the response of transport channels of intact RBC membranes upon AgNO3 administration: an atomic force microscopy study.

BACKGROUND/AIMS: Cell membranes facilitate the transport of water, ions, and necessary nutrients by hosting a great variety of transport channels that have either a 'simple' pore-like structure or more complex architecture that is based on the utilization of specific receptors. The present study reveals the impact of AgNO3, a well-known inhibitor of water channel activity, on transport channels that emerge at the membrane of intact red blood cells (iRBCs). METHODS: Atomic force microscopy is employed to survey the morphological modification of all transport channels by directly comparing the respective images obtained on the exact same iRBCs prior to and after spraying the AgNO3 solution. RESULTS: Small pores of mean size 50 nm that were assigned to water channels, and extended orifices of mean size 300 nm that exhibit a neck-like extracellular segment were observed at the iRBC membrane. CONCLUSION: Our results reveal that AgNO3 exerts noticeable influence on all transport channels so that its selective water channel inhibitory action should be reconsidered. For low AgNO3 concentrations extended recovery of the small pore network was observed upon waiting, giving strong evidence that iRBCs have a recovery potential upon simply removing the inhibition cause without the need for specific reducing agents.

Nanobiotechnology for the prevention of dialysis-related amyloidosis.

Dialysis-related amyloidosis is related to the inefficient removal of beta(2)-microglobulin (beta(2)-m) that is mainly responsible for the formation of amyloid fibrils deposited on the joints and in the heart, blood vessels and digestive system. Magnetically assisted hemodialysis (MAHD) can be used for the prevention of dialysis-related amyloidosis. MAHD is based on ferromagnetic nanoparticle-targeted binding substance conjugates (FN-TBS Cs) that should be administered to the patient before the dialysis session. The TBS should have a high affinity for beta(2)-m so that the conjugates bind with the beta(2)-m in the bloodstream. The complex FN-TBS-beta(2)-m will be selectively removed during dialysis by means of a "magnetic dialyzer" that is installed at the dialysis machine in series to the conventional dialyzer. We have examined the in vitro applicability of MAHD by employing biocompatible Fe(3)O(4) and bovine serum albumin (BSA) as constituents of the FN-TBS Cs. We evaluated the binding capacity of both bare Fe(3)O(4) FNs and Fe(3)O(4)-BSA Cs for beta(2)-m concentrations ranging from mild to severe conditions. Finally, we conducted mock-dialysis experiments for the evaluation of several technical issues related to MAHD. beta(2)-m is adsorbed onto the Fe(3)O(4)-BSA Cs not only almost instantly, but also very efficiently. The employed Cs do not chemically interact with the materials used in standard dialyzers, as agglomerates were not observed in the capillaries of the conventional dialyzers. MAHD may become an efficient modality for the prevention of dialysis-related amyloidosis because beta(2)-m concentrations ranging from mild to severe conditions can be adequately handled.

Utilization of nanobiotechnology in haemodialysis: mock-dialysis experiments on homocysteine.

BACKGROUND: The utilization of modern achievements from nanobiotechnology has resulted in novel modalities for renal replacement therapy. For conventional intermittent haemodialysis (HD), sophisticated membranes are currently being manufactured that guarantee selective removal of target toxins. These membranes have a narrow pore-size distribution that is focused around a mean value at the nanometre level. For continuous HD, novel artificial renal devices are currently being designed and evaluated in in vitro experiments that will be both implantable and have continuous function. METHODS: We present mock-dialysis experiments using magnetically assisted HD (MAHD) that we very recently introduced for the selective removal of target toxins. MAHD is based on the preparation of conjugates (Cs) made up of biocompatible ferromagnetic nanoparticles (FNs) and a specifically designed targeted binding substance that must have a high affinity for a specific target toxin substance. The FN-targeted binding substance Cs should be administered to the patient prior to MAHD to allow for binding with the target toxin substance in the bloodstream. The complex FN-targeted binding substance-target toxin substance will then be removed by a 'magnetic dialyzer' that is installed in the dialysis machine in series to the conventional dialyzer. In the present work, we compared the in vitro efficiency of MAHD to conventional HD for the removal of homocysteine (Hcy) during mock-dialysis experiments. RESULTS: These mock-dialysis experiments performed on Hcy revealed that both the removal rate and the overall removal efficiency of MAHD were significantly greater than conventional HD. CONCLUSIONS: MAHD appears to be a promising method that can be employed for the selective and more efficient extraction of toxins that are not adequately removed by conventional HD.