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Manganese-based MRI contrast agents have recently attracted much attention as an alternative to Gd-based compounds. Various nanostructures have been proposed for potential applications in in vivo diagnostics and theranostics. This review is focused on the discussion of different types of Mn oxide-based nanoparticles (MnxOy NPs) obtained at the +2, +3 and +4 oxidation states for MRI, multimodal imaging or theranostic applications. These NPs show favorable magnetic properties, good biocompatibility, and an improved toxicity profile relative to Gd(III)-based nanosystems, showing that the Mn paramagnetic ions offer advantages for the next generation of nanoscale MRI and theranostic contrast agents. Their potential for enhancing relaxivity and MRI contrast effects is illustrated through discussion of selected examples published in the past decade.

Magnetic nanoparticles (MNPs), either paramagnetic or superparamagnetic depending on their composition and size, have been thoroughly studied as magnetic resonance imaging (MRI) contrast agents using in vitro and in vivo biomedical preclinical studies, while some are clinically used. Their magnetic properties responsible in some cases for high magnetization values, together with large surface area-to-volume ratios and the possibility of surface functionalization, have been used in MRI-based diagnostic and theranostics applications. MNPs are usually used as positive (T1) or negative (T2) MRI contrast agents, causing brightening or darkening of selected regions in MRI images, respectively. This review focusses on recent developments and optimization of MNPs containing Gd, Mn, Fe and other lanthanide ions which may function as dual-mode T1–T2 MRI contrast agents (DMCAs). They induce positive or negative contrast in the same MRI scanner upon changing its operational mode between T1-weighted and T2-weighted pulse sequences. The type of contrast they induce depends critically on their r2/r1 relaxivity ratio, which for DMCAs should be in the 2–10 range of values. After briefly discussing the basic principles of paramagnetic relaxation in MNPs, in this review, the basic strategies for the rational design of DMCAs are presented and typical examples are discussed, including in vivo preclinical applications: (1) the use of NPs with a single type of contrast material, Gd- or Mn-based NPs or superparamagnetic NPs with appropriate size and magnetization to provide T2 and T1 contrast; and (2) inclusion of both types of T1 and T2 contrast materials in the same nanoplatform by changing their relative positions.

Abstract Background Excessive lactate production, a hallmark of cancer, is largely formed by the reduction of pyruvate via lactate dehydrogenase (LDH) to l-lactate. Although d-lactate can also be produced from glucose via the methylglyoxal pathway in small amounts, less is known about the amount of d-lactate produced in cancer cells. Since the stereoisomers of lactate cannot be distinguished by conventional 1H NMR spectroscopy, a chiral NMR shift reagent was used to fully resolve the 1H NMR resonances of d- and l-lactate. Methods The production of l-lactate from glucose and d-lactate from methylglyoxal was first demonstrated in freshly isolated red blood cells using the chiral NMR shift reagent, YbDO3A-trisamide. Then, two different cell lines with high GLO1 expression (H1648 and H 1395) were selected from a panel of over 80 well-characterized human NSCLC cell lines, grown to confluence in standard tissue culture media, washed with phosphate-buffered saline, and exposed to glucose in a buffer for 4 h. After 4 h, a small volume of extracellular fluid was collected and mixed with YbDO3A-trisamide for analysis by 1H NMR spectroscopy. Results A suspension of freshly isolated red blood cells exposed to 5mM glucose produced l-lactate as expected but very little d-lactate. To evaluate the utility of the chiral NMR shift reagent, methylglyoxal was then added to red cells along with glucose to stimulate the production of d-lactate via the glyoxalate pathway. In this case, both d-lactate and l-lactate were produced and their NMR chemical shifts assigned. NSCLC cell lines with different expression levels of GLO1 produced both l- and d-lactate after incubation with glucose and glutamine alone. A GLO1-deleted parental cell line (3553T3) showed no production of d-lactate from glucose while re-expression of GLO1 resulted in higher production of d-lactate. Conclusions The shift-reagent-aided NMR technique demonstrates that d-lactate is produced from glucose in NSCLC cells via the methylglyoxal pathway. The biological role of d-lactate is uncertain but a convenient method for monitoring d-lactate production could provide new insights into the biological roles of d- versus l-lactate in cancer metabolism.

Molecular recognition involving glycoprotein-mediated interactions is ubiquitous in both normal and pathological natural processes. Therefore, visualization of these interactions and the extent of expression of the sugars is a challenge in medical diagnosis, monitoring of therapy, and drug design. Here, we review the literature on the development and validation of probes for magnetic resonance imaging using carbohydrates either as targeting vectors or as a target. Lectins are important targeting vectors for carbohydrate end groups, whereas selectins, the asialoglycoprotein receptor, sialic acid end groups, hyaluronic acid, and glycated serum and hemoglobin are interesting carbohydrate targets.

The N-alkylation of 1,3,5-triaza-7-phosphaadamantane (PTA) with ortho-, meta- and para-substituted nitrobenzyl bromide under mild conditions afforded three hydrophilic PTA ammonium salts, which were used to obtain a new set of seven water-soluble copper(I) complexes. The new compounds were fully characterized and their catalytic activity was investigated for the low power microwave assisted one-pot azide–alkyne cycloaddition reaction in homogeneous aqueous medium to obtain disubstituted 1,2,3-triazoles. The most active catalysts were immobilized on activated carbon (AC), multi-walled carbon nanotubes (CNT), as well as surface functionalized AC and CNT, with the most efficient support being the CNT treated with nitric acid and NaOH. In the presence of the immobilized catalyst, several 1,4-disubstituted-1,2,3-triazoles were obtained from the reaction of terminal alkynes, organic halides and sodium azide in moderate yields up to 80%. Furthermore, the catalyzed reaction of terminal alkynes, formaldehyde and sodium azide afforded 2-hydroxymethyl-2H-1,2,3-triazoles in high yields up to 99%. The immobilized catalyst can be recovered and recycled through simple workup steps and reused up to five consecutive cycles without a marked loss in activity. The described catalytic systems proceed with a broad substrate scope, under microwave irradiation in aqueous medium and according to “click rules”.

The thermodynamic, kinetic, and structural properties of Ln3+ complexes with the bifunctional DO3A-ACE4− ligand and its amide derivative DO3A-BACE4− (modelling the case where DO3A-ACE4− ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd3+ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg2+ and Ca2+ complexes of DO3A-ACE4− and DO3A-BACE4− complexes are lower than for DOTA4− and DO3A3−, while the Zn2+ and Cu2+ complexes have similar and higher stability than for DOTA4− and DO3A3− complexes. The stability constants of the Ln(DO3A-BACE)− complexes increase from Ce3+ to Gd3+ but remain practically constant for the late Ln3+ ions (represented by Yb3+). The stability constants of the Ln(DO3A-ACE)4− and Ln(DO3A-BACE)4− complexes are several orders of magnitude lower than those of the corresponding DOTA4− and DO3A3− complexes. The formation rate of Eu(DO3A-ACE)− is one order of magnitude slower than for Eu(DOTA)−, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)− complexes to dissociate several orders of magnitude faster than Ln(DOTA)− and its absence in the Ln(DO3A-BACE)− complexes results in inertness similar to Ln(DOTA)− (as judged by the rate constants of acid assisted dissociation). The 1H NMR spectra of the diamagnetic Y(DO3A-ACE)− and Y(DO3A-BACE)− reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the Cα-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)− than the amino group in Y(DO3A-ACE)− to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)−, Gd(DO3A-BACE)− is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE4− in the design of GBCAs and Ln3+-based tags for protein structural NMR analysis.

Molecular imaging has rapidly developed to answer the need of image contrast in medical diagnostic imaging to go beyond morphological information to include functional differences in imaged tissues at the cellular and molecular levels. Vibrational (infrared (IR) and Raman) imaging has rapidly emerged among the molecular imaging modalities available, due to its label-free combination of high spatial resolution with chemical specificity. This article presents the physical basis of vibrational spectroscopy and imaging, followed by illustration of their preclinical in vitro applications in body fluids and cells, ex vivo tissues and in vivo small animals and ending with a brief discussion of their clinical translation. After comparing the advantages and disadvantages of IR/Raman imaging with the other main modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography/single-photon emission-computed tomography (PET/SPECT), ultrasound (US) and photoacoustic imaging (PAI), the design of multimodal probes combining vibrational imaging with other modalities is discussed, illustrated by some preclinical proof-of-concept examples.

A semi-empirical equation to estimate the hydration number of Mn(II) complexes was derived from a database of 49 previously published 1H longitudinal Nuclear Magnetic Relaxation Dispersion profiles. This equation has the longitudinal 1H relaxivity and the molecular weight of the Mn(II) complex under consideration as parameters.

A series of zeolite-type silicates containing stoichiometric amounts of Ln3+ ions in the framework (Ln-AV-9 materials), with composition (Na4K2)(Ln2Si16O38)·10H2O (Ln = Nd, Sm, Eu, Tb, Gd, Dy) has recently been synthesized and characterized. They form paramagnetic microparticles, which as aqueous suspensions have negligible water 1H longitudinal relaxivities (r1) for all Ln3+ ions studied and quite large transverse relaxivities (r2). In this work we further analysed the size distribution of the Ln-AV-9 particles and their r2* and r2 relaxivities. The r2* relaxivity effects are explained by the static dephasing regime (SDR) theory. The r2 relaxivities appear to be strongly dependent on the interval between two consecutive refocusing pulses (τCP) in the train of 180° pulses applied. For long τCP values, the r2 of the systems saturates at a value, which is always an order of magnitude smaller than r2*. These features are explained by a crude model, which takes into account the residual diffusion effect in the static dephasing regime. The large microparticles, although not efficient in T1 relaxation, are quite effective in enhancing T2 relaxation, particularly at high magnetic fields. The r2* values and the saturation values for r2 were found to increase linearly with B0 and μ02. The largest transversal relaxation rate enhancements were observed for Dy-AV-9 with a saturation value of r2 of 60 s−1 mM−1 and a r2* value of 566 s−1 mM−1 at 9.4 T and 298 K. [ABSTRACT FROM AUTHOR]

Glucose metabolism in five healthy subjects fasted for 16 h was measured with a combination of [U-13C]glucose and 2H2O tracers. Phenylbutyric acid was also provided to sample hepatic glutamine for the presence of 13C-isotopomers derived from the incorporation of [U-13C]glucose products into the hepatic Krebs cycle. Glucose production (GP) was quantified by 13C NMR analysis of the monoacetone derivative of plasma glucose following a primed infusion of [U-13C]glucose and provided reasonable estimates (1.90 ± 0.19 mg/kg/min with a range of 1.60–2.15 mg/kg/min). The same derivative yielded measurements of plasma glucose 2H-enrichment from 2H2O by 2H NMR from which the contribution of glycogenolytic and gluconeogenic fluxes to GP was obtained (0.87 ± 0.14 and 1.03 ± 0.10 mg/kg/min, respectively). Hepatic glutamine 13C-isotopomers representing multiply-enriched oxaloacetate and [U-13C]acetyl-CoA were identified as multiplets in the 13C NMR signals of the glutamine moiety of urinary phenylacetylglutamine, demonstrating entry of the [U-13C]glucose tracer into both oxidative and anaplerotic pathways of the hepatic Krebs cycle. These isotopomers contributed 0.1–0.2% excess enrichment to carbons 2 and 3 and ~0.05% to carbon 4 of glutamine. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This work reports on highly fluorescent and superparamagnetic bimodal nanoparticles (BNPs) obtained by a simple and efficient method as probes for fluorescence analysis and/or contrast agents for MRI. These promising BNPs with small dimensions (ca. 17 nm) consist of superparamagnetic iron oxide nanoparticles (SPIONs) covalently bound with CdTe quantum dots (ca. 3 nm). The chemical structure of the magnetic part of BNPs is predominantly magnetite, with minor goethite and maghemite contributions, as shown by Mössbauer spectroscopy, which is compatible with the x-ray diffraction data. Their size evaluation by different techniques showed that the SPION derivatization process, in order to produce the BNPs, does not lead to a large size increase. The BNPs saturation magnetization, when corrected for the organic content of the sample, is ca. 68 emu g−1, which is only slightly reduced relative to the bare nanoparticles. This indicates that the SPION surface functionalization does not change considerably the magnetic properties. The BNP aqueous suspensions presented stability, high fluorescence, high relaxivity ratio (r2/r1 equal to 25) and labeled efficiently HeLa cells as can be seen by fluorescence analysis. These BNP properties point to their applications as fluorescent probes as well as negative T2-weighted MRI contrast agents. Moreover, their potential magnetic response could also be used for fast bioseparation applications. [ABSTRACT FROM AUTHOR]

Sources of plasma glucose excursions (PGE) following a glucose tolerance test enriched with [U-(13)C]glucose and deuterated water were directly resolved by (13)C and (2)H Nuclear Magnetic Resonance spectroscopy analysis of plasma glucose and water enrichments in rat. Plasma water (2)H-enrichment attained isotopic steady-state within 2-4 minutes following the load. The fraction of PGE derived from endogenous sources was determined from the ratio of plasma glucose position 2 and plasma water (2)H-enrichments. The fractional gluconeogenic contributions to PGE were obtained from plasma glucose positions 2 and 5 (2)H-positional enrichment ratios and load contributions were estimated from plasma [U-(13)C]glucose enrichments. At 15 minutes, the load contributed 26±5% of PGE while 14±2% originated from gluconeogenesis in healthy control rats. Between 15 and 120 minutes, the load contribution fell whereas the gluconeogenic contribution remained constant. High-fat fed animals had significant higher 120-minute blood glucose (173±6 mg/dL vs. 139±10 mg/dL, p