Proton Relaxation Rates Research Articles

Criteria of the phenomenon of "magnetic relaxation switching" for the characteristics of magnetic nanoparticles (cluster model)

Diagnosis of cancer at an early stage of development is a problem of paramount importance. One of the diagnostic methods is based on the use of magnetic nanoparticles that create a magnetically active shell around the diseased tissue. Direct interaction of magnetic nanoparticles with the spins of neighbouring protons of biological fluid increases their dephasing, and at the same time the relaxation rate. The diagnostic method based on increasing the relaxation rate of water protons is called "magnetic-relaxation" switching. In this work, the criteria for observing "MR switching" for the minimum concentration of magnetic nanoparticles are obtained. Criteria for the product of the volume of diseased tissue and the characteristics of nanoparticles are also obtained.

Enzyme-free magnetic relaxation detection for glucose based on the Mn(IV)/Mn(II) conversion under alkaline condition

Herein, we have developed two enzyme-free magnetic relaxation assays for the detection of glucose utilizing the principle that glucose reduces Mn(IV) species to Mn(OH)2 in an alkaline environment, and the further conversion of Mn(OH)2 to Mn2+ under neutral condition can induce a noteworthy increase in the transverse relaxation rate (1/T2) of water protons. Thus, MnO2 nanosheets were first employed as probes and signaling units for the magnetic relaxation detection of glucose, achieving a detection limit of 1 μM. Furthermore, we realized straightforward magnetic relaxation detection of glucose by direct mixing of Mn2+ ions, NaOH and glucose in solution. This process encompasses the in-situ oxidation of Mn2+ ions to MnO(OH)2 and the subsequent reduction of MnO(OH)2 by glucose to Mn(OH)2, thereby integrating probe synthesis, and target identification within a one-pot reaction. To our knowledge, this type of analysis is more superior compared with the approach utilizing MnO2 nanosheets, since it exhibits higher sensitivity (with a limit of detection at 0.6 μM), faster, and enhanced convenience. Considering the advantages of being enzyme-free and facile, the magnetic relaxation sensing strategy, grounded in the redox reaction of Mn(IV) and glucose, holds substantial potential for diverse applications.

T1-mapping characterization of two tumor types

T1 mapping is a quantitative method to characterize tissues with magnetic resonance imaging in a quick and efficient manner. It utilizes the relaxation rate of protons to depict the underlying structures within the imaging frame. While T1-mapping techniques are used with some frequency in areas such as cardiac imaging, their application for understanding malignancies and identifying tumor structures has yet to be thoroughly investigated. Utilizing a saturation recovery method to acquire T1 maps for two different tumor models has revealed that longitudinal relaxation mapping is sensitive enough to distinguish between normal and malignant tissue. This is seen even with decreased signal/noise ratios using small voxel sizes to obtain high-resolution images. In both tumor models, it was revealed that relaxation mapping recorded significantly different relaxation values between regions encapsulating the tumor, muscle, kidney, or spleen, as well as between the cell lines themselves. This indicates a potential future application of relaxation mapping as a method to fingerprint various stages of tumor development and may prove a useful measure to identify micro-metastases.

Characterization of an enhanced formulation N-(3-methoxypropyl) acrylamide polymer gel dosimeter by the addition of an organic sensitizer for clinical practice

Polymer gel dosimeters are being developed and improved to perform measurements of radiation dose distributions in 3-dimensions (3-D) for the purpose of patient specific quality assurance for cancer patients and the configuration of treatment planning systems. The effect of organic glucose sensitizer (GL) material on N-(3-methoxypropyl) acrylamide polymer gel dosimeter (NMPAGAT) was presented in this study and evaluated after irradiation using nuclear magnetic resonance (NMR) read-out technique in terms of spin–spin relaxation rate (R2) of hydrogen protons within the water molecule. The improved tissue equivalent polymers of GL-NMPAGAT were irradiated using a medical linear accelerator with photon beams with doses up to 20 Gy, energies range 6–15 MV, dose rates range 50–500 cGy/min, and irradiation temperatures range 15–25 °C. The R2 dose sensitivity of GL-NMPAGT polymer with a concentration of 25 % wt GL was improved significantly and found to be two times higher than the same gel without GL in the linear dose response of 0.07–8 Gy. The 0.07 Gy represents the minimum detectable dose in the improved dosimeters. The dosimeter was found stable within a period of up to two weeks after irradiation, which is significant. No significant dose rate, energy dependence, and irradiation temperature for the dosimeter was observed over the range studied. There is decrease in R2 values with increasing scanning temperature. The gel is water equivalent and has theoretical energy-independent response from 0.1 to 20 MeV with density of 1.023 ± 0.003 g/cm3 and Zeff of 7.53. The results of the improved dosimeter in this study (i.e., 100 %, 0.32 s−1 Gy−1, and 8 Gy linearity) are toward the upper limit compared to other polymer gel dosimeters even with sensitizer additives.

X-ray-Sensitive Doped CaF2-Based MRI Contrast Agents for Local Radiation Dose Measurement.

Ionizing radiation has become widely used in medicine, with application in diagnostic techniques, such as computed tomography (CT) and radiation therapy (RT), where X-rays are used to diagnose and treat tumors. The X-rays used in CT and, in particular, in RT can have harmful side effects; hence, an accurate determination of the delivered radiation dose is of utmost importance to minimize any damage to healthy tissues. For this, medical specialists mostly rely on theoretical predictions of the delivered dose or external measurements of the dose. To extend the practical use of ionizing radiation-based medical techniques, such as magnetic resonance imaging (MRI)-guided RT, a more precise measurement of the internal radiation dose internally is required. In this work, a novel approach is presented to measure dose in liquids for potential future in vivo applications. The strategy relies on MRI contrast agents (CAs) that provide a dose-sensitive signal. The demonstrated materials are (citrate-capped) CaF2 nanoparticles (NPs) doped with Eu3+ or Fe2+/Fe3+ ions. Free electrons generated by ionizing radiation allow the reduction of Eu3+, which produces a very small contrast in MRI, to Eu2+, which induces a strong contrast. Oxidative species generated by high-energy X-rays can be measured indirectly using Fe2+ because it oxidizes to Fe3+, increasing the contrast in MRI. Notably, in the results, a strong increase in the proton relaxation rates is observed for the Eu3+-doped NPs at 40 kV. At 6 MV, a significant increase in proton relaxation rates is observed using CaF2 NPs doped with Fe2+/Fe3+ after irradiation. The presented concept shows great promise for use in the clinic to measure in vivo local ionizing radiation dose, as these CAs can be intravenously injected in a saline solution.

Constructing a novel pH-mediated magnetic relaxation sensor via the Mn(II)/Mn(IV) conversion

Herein, we demonstrate a new concept of chemical sensing for the construction of pH-mediated magnetic sensors. The strategy is based on the notion that the oxidation of paramagnetic Mn2+ ions to insoluble Mn(IV)O(OH)2 by dissolved oxygen under alkaline conditions can lead to a significant decrease in the transverse relaxation rate (1/T2) of water protons. Crucially, the conversion of Mn2+ ions to MnO(OH)2 correlates with the amount of NaOH, that is, the reaction is pH-dependent. Thus, by combining this reaction with enzymatic reactions that cause pH changes, we can construct pH-mediated chemical sensors based on magnetic relaxation principles. In this work, we selected glucose and urea as model substrates to verify the feasibility of this strategy, since the oxidation of glucose by glucose oxidase and the hydrolysis of urea by urease lead to a notable decrease and increase of pH, respectively, thereby causing a change in the 1/T2 of the solution. Experimental results showed that the linear detection range was 20–2000 µM with a detection limit of 10 µM for glucose, and 50–1000 µM with a detection limit of 20 µM for urea, validating the proof of concept and potential broad applicability of this strategy.

Relationship of Iron Intake, Ferritin, and Hepcidin with the Transverse Relaxation Rate of Water Protons in the Pancreas.

(1) Background: There is a paucity of markers of iron metabolism in health and disease. The aim was to investigate the associations of iron metabolism with pancreas transverse water proton relaxation rate (R2water) in healthy individuals and people after an attack of pancreatitis. (2) Methods: All participants underwent a 3.0 T magnetic resonance imaging of the abdomen on the same scanner. High-speed T2-corrected multi-echo (HISTO) acquisition at single-voxel magnetic resonance spectroscopy and inline processing were used to quantify pancreas R2water. Habitual dietary intake of iron was determined using the EPIC-Norfolk food frequency questionnaire. Circulating levels of ferritin and hepcidin were measured. Generalised additive models were used, adjusting for age, sex, body mass index, and haemoglobin A1c. (3) Results: A total of 139 individuals (47 healthy individuals, 54 individuals after acute pancreatitis, and 38 individuals after chronic pancreatitis) were included. Total dietary intake of iron was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p < 0.001) across all the statistical models. Ferritin was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p = 0.01) across all adjusted models. Hepcidin was significantly associated with pancreas R2water in individuals after acute pancreatitis (p < 0.001) and individuals after chronic pancreatitis (p = 0.04) in the most adjusted model. (4) Conclusions: Pancreas R2water, corrected for T2, is related to iron metabolism in both health and pancreatitis. This non-invasive marker could be used for automated in vivo identification of intra-pancreatic iron deposition.

Molecular-Level Structural Analysis of siRNA-Loaded Lipid Nanoparticles by 1H NMR Relaxometry: Impact of Lipid Composition on Their Structural Properties.

1H NMR relaxometry was applied for molecular-level structural analysis of siRNA-loaded lipid nanoparticles (LNPs) to clarify the impact of the neutral lipids, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, on the physicochemical properties of LNP. Incorporating DSPC and cholesterol in ionizable lipid-based LNP decreased the molecular mobility of ionizable lipids. DSPC reduced the overall molecular mobility of ionizable lipids, while cholesterol specifically decreased the mobility of the hydrophobic tails of ionizable lipids, suggesting that cholesterol filled the gap between the hydrophobic tails of ionizable lipids. The decrease in molecular mobility and change in orientation of lipid mixtures contributed to the maintenance of the stacked bilayer structure of siRNA and ionizable lipids, thereby increasing the siRNA encapsulation efficiency. Furthermore, NMR relaxometry revealed that incorporating those neutral lipids enhanced PEG chain flexibility at the LNP interface. Notably, a small amount of DSPC effectively increased PEG chain flexibility, possibly contributing to the improved dispersion stability and narrower size distribution of LNPs. However, cryogenic transmission electron microscopy represented that adding excess amounts of DSPC and cholesterol into LNP resulted in the formation of deformed particles and demixing cholesterol within the LNP, respectively. The optimal lipid composition of ionizable lipid-based LNPs in terms of siRNA encapsulation efficiency and PEG chain flexibility was rationalized based on the molecular-level characterization of LNPs. Moreover, the NMR relaxation rate of tertiary amine protons of ionizable lipids, which are the interaction site with siRNA, can be a valuable indicator of the encapsulated amount of siRNA within LNPs. Thus, NMR-based analysis can be a powerful tool for efficiently designing LNP formulations and their quality control based on the molecular-level elucidation of the physicochemical properties of LNPs.

Near infrared-emitting multimodal nanosystem for in vitro magnetic hyperthermia of hepatocellular carcinoma and dual imaging of in vivo liver fibrosis

Prolonged usage of traditional nanomaterials in the biological field has posed several short- and long-term toxicity issues. Over the past few years, smart nanomaterials (SNs) with controlled physical, chemical, and biological features have been synthesized in an effort to allay these challenges. The current study seeks to develop theranostic SNs based on iron oxide to enable simultaneous magnetic hyperthermia and magnetic resonance imaging (MRI), for chronic liver damage like liver fibrosis which is a major risk factor for hepatocellular carcinoma. To accomplish this, superparamagnetic iron oxide nanoparticles (SPIONs) were prepared, coated with a biocompatible and naturally occurring polysaccharide, alginate. The resultant material, ASPIONs were evaluated in terms of physicochemical, magnetic and biological properties. A hydrodynamic diameter of 40 nm and a transverse proton relaxation rate of 117.84 mM−1 s−1 pronounces the use of ASPIONs as an efficient MRI contrast agent. In the presence of alternating current of 300 A, ASPIONs could elevate the temperature to 45 °C or more, with the possibility of hyperthermia based therapeutic approach. Magnetic therapeutic and imaging potential of ASPIONs were further evaluated respectively in vitro and in vivo in HepG2 carcinoma cells and animal models of liver fibrosis, respectively. Finally, to introduce dual imaging capability along with magnetic properties, ASPIONs were conjugated with near infrared (NIR) dye Atto 700 and evaluated its optical imaging efficiency in animal model of liver fibrosis. Histological analysis further confirmed the liver targeting efficacy of the developed SNs for Magnetic theranostics and optical imaging as well as proved its short-term safety, in vivo.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1=1.90±0.12 mM-1 s-1 and r2=12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Sometimes pulses just have to be perfect – An example based on the measurement of amide proton transverse relaxation rates in proteins

The measurement of spin relaxation rates provides a unique avenue for quantifying dynamic processes in biomolecules. In order to simplify analysis of the measurements so that a few key intuitive parameters can be extracted, it is often the case that experiments are designed to eliminate interference effects between different classes of spin relaxation. One example emerges in the measurement of amide proton (1HN) transverse relaxation rates in 15N labeled proteins, where 15N inversion pulses are applied during a relaxation element to eliminate cross-correlated spin relaxation between 1HN-15N dipole-1HN CSA interactions. We show that unless these pulses are essentially perfect, significant oscillations in magnetization decay profiles can be obtained, due to the excitation of multiple-quantum coherences, leading potentially to errors in measured R2 rates. With the recent development of experiments for quantifying electrostatic potentials via amide proton relaxation rates, the need for highly accurate measurement schemes becomes critical. Straightforward modifications to existing pulse sequences are suggested to achieve this goal.

Peptide-Based Hydrogels and Nanogels Containing Gd(III) Complexes as T1 Relaxation Agents.

New peptide-based hydrogels incorporating Gd(III) chelates with different hydration states, molecular structures and overall negative charges ([Gd(BOPTA)]2-), [Gd(DTPA)]2-, and ([Gd(AAZTA)]-) were prepared and characterized. N-terminal Fmoc- or acetyl-derivatized hexapeptides (K1, K2 and K3) containing five aliphatic amino acids (differently ordered Gly, Ala, Val, Leu and Ile) and a charged lysine at the amidated C-terminal were used for the formation of the hydrogels. Particular attention was paid to the investigation of the morphological and rheological properties of the nanoparticles, in addition to the assessment of the ability (relaxivity) of the confined complexes to accelerate the longitudinal relaxation rate of the water protons localized in the polymeric network. The relaxivity values at high magnetic fields (&gt;0.5 T) of the paramagnetic hydrogels appear to be more than five times higher than those of isolated chelates in an aqueous solution, reaching a value of 25 mmol-1 s-1 for Fmoc-K2+[Gd(BOPTA)]2- at 0.5 T and 310 K. Furthermore, an interesting trend of decrease of relaxivity with increasing the degree of rigidity of the hydrogel was observed. The type of interactions between the various complexes and the polymeric network also plays a key role in influencing the relaxivity values of the final materials. Nanogels were also obtained from the submicronization of the hydrogel containing [Gd(BOPTA)]2- chelate. Circular dichroism, dynamic light scattering and relaxometric investigations on these nanoparticles revealed the formation of nanogels endowed with higher relaxivities (r1 = 41 mM-1 s-1 at 0.5 T MHz and 310 K) than the corresponding hydrogels.

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field.

Simple SummarySince the pioneering work of Damadian (1971), the longitudinal T1-relaxation of nuclear magnetic resonance (NMR) has been reported to generate significant contrast between cancer and healthy tissues at low magnetic fields. However, low NMR sensitivity was a substantial obstacle. Fast field cycling NMR (FFC-NMR) can overcome this problem and is commercially available for physics/chemistry research since around the years 2000s. Herein, using FFC-NMR in vivo, we show that T1-relaxation measured at very low fields is sensitive to transmembrane water exchange, thus allowing the discrimination between glioma invasion/migration and proliferation. Aquaporins 4 and 1 are found to be upregulated in invasion/migration, indicating that water exchange modulates T1-relaxations in glioma, via these aquaporins action. Overall, results suggest that, by blocking the aquaporin functions, the T1-relaxation should decrease in invasion/migration glioma. Results also stipulate that the entire invasion/migration volume could be visualized by FFC imaging, noninvasively. This may impact the medical community since invasion/migration delineation remains challenging by any medical imaging modality.This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.

Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model.

This study aims to explore whether the water exchange rate constants in tumor cells can act as a hallmark of pathology status and a reporter of therapeutic outcomes. It has been shown, using 4T1 cell cultures and murine allografts, that an early assessment of the therapeutic effect of doxorubicin can be detected through changes in the cellular water efflux rate constant kio. The latter has been estimated by analyzing the magnetization recovery curve in standard NMR T1 measurements when there is a marked difference in the proton relaxation rate constants (R1) between the intra- and the extra-cellular compartments. In cellular studies, T1 measurements were carried out on a relaxometer working at 0.5 T, and the required difference in R1 between the two compartments was achieved via the addition of a paramagnetic agent into the extracellular compartment. For in-vivo experiments, the large difference in the R1 values of the two-compartments was achieved when the T1 measurements were carried out at low magnetic field strengths. This task was accomplished using a Fast Field Cycling (FFC) relaxometer that was properly modified to host a mouse in its probe head. The decrease in kio upon the administration of doxorubicin is the result of the decreased activity of Na+/K+-ATPase, as shown in an independent test on the cellular uptake of Rb ions. The results reported herein suggest that kio can be considered a non-invasive, early and predictive biomarker for the identification of responsive patients immediately from the first doxorubicin treatment.

Rapid and Noninvasive Quantification of Capsid Gene Filling Level Using Water Proton Nuclear Magnetic Resonance.

The present work reports an enabling novel technology for quantifying the gene content in adeno-associated viral capsids. The method is based on the water proton nuclear magnetic resonance (wNMR) technique. Instead of analyzing the capsid directly, it utilizes water molecules to distinguish empty and full capsids, as water interacts with them differently. The transverse relaxation rate of water protons, R2(1H2O), readily distinguishes empty and full capsids and is capable of quantifying the fraction of full capsids in a mixture of full and empty ones. It involves no sample preparation and no reagents. Measurement is rapid (data collection takes 1-2 min), noninvasive (the capsid sample can stay inside the original sealed and labeled container to be used in other studies or administered to a patient), and performed using a wide-bore benchtop NMR instrument. The method can be readily implemented at a production plant for product release as part of product quality control.

Liposomal Fe(III) Macrocyclic Complexes with Hydroxypropyl Pendants as MRI Probes.

Paramagnetic liposomes containing Fe(III) complexes were prepared by incorporation of mononuclear (Fe(L1) or Fe(L3)) or dinuclear (Fe2(L2)) coordination complexes of 1,4,7-triazacyclononane macrocycles containing 2-hydroxypropyl pendant groups. Two different types of paramagnetic liposomes were prepared. The first type, LipoA, has the mononuclear Fe(L1) complex loaded into the internal aqueous core. The second type, LipoB, has the amphiphilic Fe(L3) complex inserted into the liposomal bilayer and the internal aqueous core loaded with either Fe(L1) (LipoB1) or Fe2(L2) (LipoB2). LipoA enhances both T1 and T2 water proton relaxation rates. Treatment of LipoA with osmotic gradients to produce a nonspherical liposome produces a liposome with a chemical exchange saturation transfer effect as shown by an asymmetry analysis but only at high osmolarity. LipoB1, which contains an amphiphilic complex in the liposomal bilayer, produced a broadened Z-spectrum upon treatment of the liposome with osmotic gradients. The r1 relaxivity of LipoB1 and LipoB2 were higher than the r1 relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe(III) center. The r1 relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4-9.4 T), with the ratio of r2/r1 substantially increasing at high field strengths. MRI studies of LipoB1 in mice showed prolonged contrast enhancement in blood compared to the clinically employed Gd(DOTA), which was injected at a 2-fold higher dose per metal than the Fe(III)-loaded liposomes.

Low-Field NMR Relaxometry for Intraoperative Tumour Margin Assessment in Breast-Conserving Surgery.

Simple SummaryBreast cancer is the most diagnosed cancer for women, and clear surgical margins in breast-conserving surgery (BCS) are essential for preventing recurrence. In this study, the potential of fast field-cycling 1H-NMR relaxometry as a new tool for intraoperative margin assessment was evaluated. The technique allows the determination of the tissue proton relaxation rates as a function of the applied magnetic field on small tissue samples excised from surgical specimens, at the margins of tumour resection, prior to histopathological analysis. It was found that a good accuracy in margin assessment, i.e., a sensitivity of 92% and a specificity of 85%, can be achieved. The discriminating ability shown by the relaxometric assay relies mainly on the difference of fat/water content between healthy and tumour cells. The information obtained has the potential to support the surgeon in real-time margin assessment during BCS.As conserving surgery is routinely applied for the treatment of early-stage breast cancer, the need for new technology to improve intraoperative margin assessment has become increasingly important. In this study, the potential of fast field-cycling 1H-NMR relaxometry as a new diagnostic tool was evaluated. The technique allows the determination of the tissue proton relaxation rates (R1), as a function of the applied magnetic field, which are affected by the changes in the composition of the mammary gland tissue occurring during the development of neoplasia. The study involved 104 small tissue samples obtained from surgical specimens destined for histopathology. It was found that a good accuracy in margin assessment, i.e., a sensitivity of 92% and a specificity of 85%, can be achieved by using two quantifiers, namely (i) the slope of the line joining the R1 values measured at 0.02 and 1 MHz and (ii) the sum of the R1 values measured at 0.39 and 1 MHz. The method is fast, and it does not rely on the expertise of a pathologist or cytologist. The obtained results suggest that a simplified, low-cost, automated instrument might compete well with the currently available tools in margin assessment.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Hydrogels for Three-Dimensional Ionizing-Radiation Dosimetry.

Radiation-sensitive gels are among the most recent and promising developments for radiation therapy (RT) dosimetry. RT dosimetry has the twofold goal of ensuring the quality of the treatment and the radiation protection of the patient. Benchmark dosimetry for acceptance testing and commissioning of RT systems is still based on ionization chambers. However, even the smallest chambers cannot resolve the steep dose gradients of up to 30–50% per mm generated with the most advanced techniques. While a multitude of systems based, e.g., on luminescence, silicon diodes and radiochromic materials have been developed, they do not allow the truly continuous 3D dose measurements offered by radiation-sensitive gels. The gels are tissue equivalent, so they also serve as phantoms, and their response is largely independent of radiation quality and dose rate. Some of them are infused with ferrous sulfate and rely on the radiation-induced oxidation of ferrous ions to ferric ions (Fricke-gels). Other formulations consist of monomers dispersed in a gelatinous medium (Polyacrylamide gels) and rely on radiation-induced polymerization, which creates a stable polymer structure. In both gel types, irradiation causes changes in proton relaxation rates that are proportional to locally absorbed dose and can be imaged using magnetic resonance imaging (MRI). Changes in color and/or opacification of the gels also occur upon irradiation, allowing the use of optical tomography techniques. In this work, we review both Fricke and polyacrylamide gels with emphasis on their chemical and physical properties and on their applications for radiation dosimetry.

Inspecting Insulin Products Using Water Proton NMR. I. Noninvasive vs Invasive Inspection.

There is a clear need to transition from batch-level to vial/syringe/pen-level quality control of biologic drugs, such as insulin. This could be achieved only by noninvasive and quantitative inspection technologies that maintain the integrity of the drug product. Four insulin products for patient self-injection presented as prefilled pens have been noninvasively and quantitatively inspected using the water proton NMR technology. The inspection output is the water proton relaxation rate R2(1H2O), a continuous numerical variable rather than binary pass/fail. Ten pens of each product were inspected. R2(1H2O) displays insignificant variation among the 10 pens of each product, suggesting good insulin content uniformity in the inspected pens. It is also shown that transferring the insulin solution out of and then back into the insulin pen caused significant change in R2(1H2O), presumably due to exposure to O2 in air. Water proton NMR can noninvasively and quantitatively inspect insulin pens. wNMR can confirm product content uniformity, but not absolute content. Its sensitivity to sample transferring provides a way to detect drug product tampering. This opens the possibility of inspecting every pen/vial/syringe by manufacturers and end-users.