We report a Co-based magnetic resonance (MR) probe that enables the ratiometric quantitation and imaging of pH through chemical exchange saturation transfer (CEST). This approach is illustrated in a series of air- and water-stable Co complexes featuring CEST-active tetra(carboxamide) and/or hydroxyl-substituted bisphosphonate ligands. For the complex bearing both ligands, variable-pH CEST and NMR analyses reveal highly shifted carboxamide and hydroxyl peaks with intensities that increase and decrease with increasing pH, respectively. The ratios of CEST peak intensities at 104 and 64 ppm are correlated with solution pH in the physiological range 6.5-7.6 to construct a linear calibration curve of log(CEST/CEST) versus pH, which exhibits a remarkably high pH sensitivity of 0.99(7) pH unit at 37 °C. In contrast, the analogous Co complex with a CEST-inactive bisphosphonate ligand exhibits no such pH response, confirming that the pH sensitivity stems from the integration of amide and hydroxyl CEST effects that show base- and acid-catalyzed proton exchange, respectively. Importantly, the pH calibration curve is independent of the probe concentration and is identical in aqueous buffer and fetal bovine serum. Furthermore, phantom images reveal analogous linear pH behavior. The Co probe is stable toward millimolar concentrations of HPO/HPO, CO, SO, CHCOO, and Ca ions, and more than 50% of melanoma cells remain viable in the presence of millimolar concentrations of the complex. The stability of the probe in physiological environments suggests that it may be suitable for in vivo studies. Together, these results highlight the ability of dinuclear transition metal PARACEST probes to provide a concentration-independent measure of pH, and they provide a potential design strategy toward the development of MR probes for ratiometric pH imaging.
We have discovered a heterogeneous catalyst that aligns the proton magnetic moments in liquid water, methanol, and ethanol molecules by using parahydrogen. In this SWAMP (surface waters are magnetized by parahydrogen) effect, hyperpolarization of the solvent protons is induced simply by the bubbling of parahydrogen gas through a suspension of the intermetallic nanoparticle catalyst in the neat liquid. The conversion of singlet spin order into magnetization is mediated by surface interactions and intermolecular spin couplings. The SWAMP effect has promising applications ranging from low-field MRI to drug discovery.
Aqueous liquid mixtures, in particular, those involving amphiphilic species, play an important role in many physical, chemical and biological processes. Of particular interest are alcohol/water mixtures; however, the structural dynamics of such systems are still not fully understood. Herein, a combination of terahertz time-domain spectroscopy (THz-TDS) and NMR relaxation time analysis has been applied to investigate 2-propanol/water mixtures across the entire composition range; while neutron diffraction studies have been carried out at two specific concentrations. Excellent agreement is seen between the techniques with a maximum in both the relative absorption coefficient and the activation energy to molecular motion occurring at ∼90 mol% H2O. Furthermore, this is the same value at which well-established excess thermodynamic functions exhibit a maximum/minimum. Additionally, both neutron diffraction and THz-TDS have been used to provide estimates of the size of the hydration shell around 2-propanol in solution. Both methods determine that between 4 and 5 H2O molecules per 2-propanol are found in the 2-propanol/water clusters at 90 mol% H2O. Based on the acquired data, a description of the structure of 2-propanol/water across the composition range is presented.
Two-dimensional T(2)-T(2) NMR relaxation exchange spectroscopy has been applied to model porous media composed of mixtures of nonporous borosilicate and soda lime glass spheres in water. The spheres had a mean diameter of 100 microm, thus providing an approximately constant characteristic pore dimension throughout the structures, while the use of two glass types ensured that water in different pore-space regions had significantly different T(2) relaxation rates. The packed beds were constructed in various ways with controlled glass type domain sizes to rigorously validate a model for region-to-region exchange of water. From the determined exchange times, the corresponding length scales were calculated based on the molecular self-diffusion of water; these agreed to better than +/-25% with the expected domain sizes. Furthermore, exchange distances on the order of the pore size were observed in thoroughly mixed systems. Depending on the relaxation rates present in the sample, this technique can provide estimates of length scales ranging from microns to millimeters.
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