Sabrina Laus

University of Geneva, Genève, Geneva, Switzerland

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Publications (11)57.02 Total impact

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    ABSTRACT: The only currently available method to measure brain glycogen in vivo is 13C NMR spectroscopy. Incorporation of 13C-labeled glucose (Glc) is necessary to allow glycogen measurement, but might be affected by turnover changes. Our aim was to measure glycogen absolute concentration in the rat brain by eliminating label turnover as variable. The approach is based on establishing an increased, constant 13C isotopic enrichment (IE). 13C-Glc infusion is then performed at the IE of brain glycogen. As glycogen IE cannot be assessed in vivo, we validated that it can be inferred from that of N-acetyl-aspartate IE in vivo: After [1-13C]-Glc ingestion, glycogen IE was 2.2 +/- 0.1 fold that of N-acetyl-aspartate (n = 11, R(2) = 0.77). After subsequent Glc infusion, glycogen IE equaled brain Glc IE (n = 6, paired t-test, p = 0.37), implying isotopic steady-state achievement and complete turnover of the glycogen molecule. Glycogen concentration measured in vivo by 13C NMR (mean +/- SD: 5.8 +/- 0.7 micromol/g) was in excellent agreement with that in vitro (6.4 +/- 0.6 micromol/g, n = 5). When insulin was administered, the stability of glycogen concentration was analogous to previous biochemical measurements implying that glycogen turnover is activated by insulin. We conclude that the entire glycogen molecule is turned over and that insulin activates glycogen turnover.
    Journal of Neurochemistry 01/2009; 107(5):1414-23. DOI:10.1111/j.1471-4159.2008.05717.x · 4.24 Impact Factor
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    ABSTRACT: With their nanoscalar, superparamagnetic Gd(3+)-ion clusters (1 x 5 nm) confined within ultrashort (20-80 nm) single-walled carbon nanotube capsules, gadonanotubes are high-performance T1-weighted contrast agents for magnetic resonance imaging (MRI). At 1.5 T, 37 degrees C, and pH 6.5, the r1 relaxivity (ca. 180 mM(-1) s(-1) per Gd(3+) ion) of gadonanotubes is 40 times greater than any current Gd(3+) ion-based clinical agent. Herein, we report that gadonanotubes are also ultrasensitive pH-smart probes with their r1/pH response from pH 7.0-7.4 being an order of magnitude greater than for any other MR contrast agent. This result suggests that gadonanotubes might be excellent candidates for the development of clinical agents for the early detection of cancer where the extracellular pH of tumors can drop to pH=7 or below. In the present study, gadonanotubes have also been shown to maintain their integrity when challenged ex vivo by phosphate-buffered saline solution, serum, heat, and pH cycling.
    Nano Letters 03/2008; 8(2):415-9. DOI:10.1021/nl0720408 · 13.59 Impact Factor
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    ABSTRACT: The relaxivity of commercially available gadolinium (Gd)-based contrast agents was studied for X-nuclei resonances with long intrinsic relaxation times ranging from 6 s to several hundred seconds. Omniscan in pure 13C formic acid had a relaxivity of 2.9 mM(-1) s(-1), whereas its relaxivity on glutamate C1 and C5 in aqueous solution was approximately 0.5 mM(-1) s(-1). Both relaxivities allow the preparation of solutions with a predetermined short T1 and suggest that in vitro substantial sensitivity gains in their measurement can be achieved. 6Li has a long intrinsic relaxation time, on the order of several minutes, which was strongly affected by the contrast agents. Relaxivity ranged from approximately 0.1 mM(-1) s(-1) for Omniscan to 0.3 for Magnevist, whereas the relaxivity of Gd-DOTP was at 11 mM(-1) s(-1), which is two orders of magnitude higher. Overall, these experiments suggest that the presence of 0.1- to 10-microM contrast agents should be detectable, provided sufficient sensitivity is available, such as that afforded by hyperpolarization, recently introduced to in vivo imaging.
    Magnetic Resonance Imaging 08/2007; 25(6):821-5. DOI:10.1016/j.mri.2007.02.015 · 2.02 Impact Factor
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    ABSTRACT: In the search for highly efficient magnetic resonance imaging contrast agents, polyamino polypyridine carboxylate complexes of Gd3+ have shown unusual properties with both very rapid and very slow electron spin relaxation in solution observed by electron paramagnetic resonance. Since the relationship between the molecular structure and the electron spin properties remains quite obscure at this point, detailed studies of such complexes may offer useful clues for the design of Gd3+ compounds with tailored electronic features. Furthermore, the availability of very high-frequency EPR spectrometers based on quasi-optical components provides us with an opportunity to test the existing relaxation theories at increasingly high magnetic fields and observation frequencies. We present a detailed EPR study of two gadolinium polyamino polypyridine carboxylate complexes, [Gd(tpaen)]- and [Gd(bpatcn)(H2O)], in liquid aqueous solutions at multiple temperatures and frequencies between 9.5 and 325 GHz. We analyze the results using the model of random zero-field splitting modulations through Brownian rotation and molecular deformations. We consider the effect of concentration on the line width, as well as the possible existence of an additional g-tensor modulation relaxation mechanism and its possible impact on future experiments. We use (17)O NMR to characterize the water exchange rate on [Gd(bpatcn)(H2O)] and find it to be slow (approximately 0.6 x 10(6) s-1).
    The Journal of Physical Chemistry A 07/2007; 111(25):5399-407. DOI:10.1021/jp066921z · 2.78 Impact Factor
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    ABSTRACT: Water-soluble, endohedral gadofullerenes exhibit considerably higher relaxivities than clinically used Gd3+-chelates and are currently explored as potential magnetic resonance imaging (MRI) contrast agents. The relaxivities of Gd@C-60(OH)(x) (x approximate to 27) and Gd@C-60[C(COOHyNa1-y)(2)](10) were previously found to vary with pH because of pH-dependent aggregation. By relaxometric measurements, we proved that aggregation can be suppressed by salt addition (75-100 equiv of sodium phosphate). In the aim of better understanding paramagnetic relaxation mechanisms in water-soluble gadofullerenes, we recorded variable-temperature and multiple-field O-17 and H-1 relaxation rates for Gd@C-60(OH)(x) and Gd@C-60[C(COOHyNa1-y)(2)](10) in both aggregated and disaggregated state (monomers). In the aggregated solutions, the O-17 T-1 and T-2 values are very different. This proves the confinement of water molecules in the interstices of the aggregates which is more important for the OH than for the malonate derivative. The rapid exchange of these water molecules with bulk contributes to the high relaxivity of the aggregated gadofullerenes. After disruption of the aggregates into distinct gadofullerene molecules, the temperature-dependent proton relaxivities could be described as the sum of an outer-sphere and an inner-sphere-like mechanism. The inner-sphere-like term originates from proton exchange between the bulk and protonated OH or COOH sites. The relaxivity peak observed between 10 and 300 MHz in the nuclear magnetic relaxation dispersion (NMRD) profile evidences that the malonate groups are at least partially protonated at pH 7.4. The rotational correlation times are long (similar to 1.2 ns) and identical for the two gadofullerenes. The larger relaxivity of Gd@C-60(OH)(x) as compared to Gd@ C-60[C(COOHxNa1-x)(2)](10) at frequencies above 20 MHz is related to the larger number of protonated sites.
    The Journal of Physical Chemistry C 04/2007; 111(15). DOI:10.1021/jp070458o · 4.84 Impact Factor
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    ABSTRACT: We report the nanoscale loading and confinement of aquated Gd3+n-ion clusters within ultra-short single-walled carbon nanotubes (US-tubes); these Gd3+n@US-tube species are linear superparamagnetic molecular magnets with Magnetic Resonance Imaging (MRI) efficacies 40 to 90 times larger than any Gd3+-based contrast agent (CA) in current clinical use.
    Chemical Communications 09/2005; DOI:10.1039/B504435A · 6.72 Impact Factor
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    ABSTRACT: A combined proton relaxivity and dynamic light scattering study has shown that aggregates formed in aqueous solution of water-soluble gadofullerenes can be disrupted by addition of salts. The salt content of fullerene-based materials will strongly influence properties related to aggregation phenomena, therefore, their behavior in biological or medical applications. In particular, the relaxivity of gadofullerenes decreases dramatically with phosphate addition. Moreover, real biological fluids present a rather high salt concentration which will have consequences on fullerene aggregation and influence fullerene-based drug delivery.
    Journal of the American Chemical Society 08/2005; 127(26):9368-9. DOI:10.1021/ja052388+ · 11.44 Impact Factor
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    ABSTRACT: Three different generations of polyamidoamine (PAMAM) dendrimers were loaded with EPTPA, a chelate that ensures fast water exchange with a Gd III complex. The dendrimeric GdIII complexes were characterized with regard to magnetic resonance imaging (MRI) contrast agent applications by proton relaxivity and 17O nuclear magnetic resonance (NMR) studies. Their proton relaxivity showed an important pH-dependency, which is related to the pH-dependent rotational dynamics. It was observed that hydrogen bonding also becomes more important at lower pH, contributing to the rigidity of the macromolecule.
    Chemistry 05/2005; 11(10):3064-76. DOI:10.1002/chem.200401326 · 5.70 Impact Factor
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    ABSTRACT: On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd(III) poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-) ligand (DTPA=(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO(2) (5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature (17)O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO(2))(H(2)O)](2-) and [Gd(eptpa)(H(2)O)](2-) than on [Gd(dtpa)(H(2)O)](2-) (k(ex)298=150x10(6), 330x10(6), and 3.3x10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure (17)O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H(2)O)](2-) (DeltaV(not equal sign)=(+6.6+/-1.0) cm(3) mol(-1)). In contrast to [Gd(eptpa)(H(2)O)](2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H(2)O)](-) (DeltaV (not equal sign)=(-1.5+/-1.0) cm(3) mol(-1)), which has one more CH(2) group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H(2)O)](-), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) is substituted by a propionate, the water exchange rate on the Gd(III) complex increases by a factor of 10 (k(ex)298=31x10(6) s(-1)). The [Gd(dptpa)](2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO(2) (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd(III), Zn(II), Cu(II) and Ca(II) were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO(2))(H(2)O)](2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H(2)O)](2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H(2)O)](-) are potential building blocks for the development of high-relaxivity macromolecular agents.
    Chemistry 08/2003; 9(15):3555-66. DOI:10.1002/chem.200204612 · 5.70 Impact Factor