PurposeTo compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium‐based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol.Materials and MethodsFifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28‐day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP‐MS).ResultsAfter 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05).ConclusionDifferences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. Level of Evidence: 2 Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2018;47:746–752.

Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early-or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at welltolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation. Cancer Res; 71(4); 1396-405. Ó2011 AACR.

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A novel mathematical treatment is proposed for computing the time evolution of dynamic nuclear polarization processes in the low temperature thermal mixing regime. Without assuming any a priori analytical form for the electron polarization, our approach provides a quantitative picture of the steady state that agrees with the well known Borghini prediction based on thermodynamic arguments, as long as the electrons-nuclei transition rates are fast compared to the other relevant time scales. Substantially different final polarization levels are achieved instead when the latter assumption is relaxed in the presence of a nuclear leakage term, even though very weak, suggesting a possible explanation for the deviation between the measured steady state polarizations and the Borghini prediction. The proposed methodology also allows to calculate nuclear polarization and relaxation times, once the electrons/nuclei concentration ratio and the typical rates of the microscopic processes involving the two spin species are specified. Numerical results are shown to account for the manifold dynamical behaviours of typical DNP samples.

We have explored the manifold physical scenario emerging from a model of Dynamic Nuclear Polarization (DNP) via thermal mixing under the hypothesis of highly effective electron-electron interaction. When the electron and nuclear reservoirs are also assumed to be in strong thermal contact and the microwave irradiation saturates the target electron transition, the enhancement of the nuclear polarization is expected to be considerably high even if the irradiation frequency is set far away from the centre of the ESR line (as already predicted by Borghini) and the typical polarization time is reduced on moving towards the boundaries of said line. More reasonable behaviours are obtained by reducing the level of microwave saturation or the contact between electrons and nuclei in presence of nuclear leakage. In both cases the function describing the dependency of the steady state nuclear polarization on the frequency of irradiation becomes sharper at the edges and the build up rate decreases on moving off-resonance. If qualitatively similar in terms of the effects produced on nuclear polarization, the degree of microwave saturation and of electron-nucleus contact has a totally different impact on electron polarization, which is of course strongly correlated to the effectiveness of saturation and almost insensitive, at the steady state, to the magnitude of the interactions between the two spin reservoirs. The likelihood of the different scenario is discussed in the light of the experimental data currently available in literature, to point out which aspects are suitably accounted and which are not by the declinations of thermal mixing DNP considered here.

Glucose is the central nervous system’s only energy source. Imaging techniques capable to detect pathological alterations of the brain metabolism are useful in different diagnostic processes. Such techniques are also beneficial for assessing the evaluation efficacy of therapies in pre-clinical and clinical stages of diseases. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a possible alternative to positron emission tomography (PET) imaging that has been widely explored in cancer research in humans and animal models. We propose that pathological alterations in brain 2-deoxy-D-glucose (2DG) uptake, typical of neurodegenerative diseases, can be detected with CEST MRI. Transgenic mice overexpressing a mutated form of amyloid precusrsor protein (APP23), a model of Alzheimer’s disease, analyzed with CEST MRI showed a clear reduction of 2DG uptake in different brain regions. This was reminiscent of the cerebral condition observed in Alzheimer’s patients. The results indicate the feasibility of CEST for analyzing the brain metabolic state, with better image resolution than PET in experimental models.

The temperature dependence of 1 H and 13 C nuclear spin-lattice relaxation rate 1/T1 has been studied in the 1.6 K -4.2 K temperature range in pure pyruvic acid and in pyruvic acid containing trityl radicals at a concentration of 15 mM. The temperature dependence of 1/T1 is found to follow a quadratic power law for both nuclei in the two samples. Remarkably the same temperature dependence is displayed also by the electron spin-lattice relaxation rate 1/T1e in the sample containing radicals. These results are explained by considering the effect of the structural dynamics on the relaxation rates in pyruvic acid. Dynamic nuclear polarization experiments show that below 4 K the 13 C build up rate scales with 1/T1e, in analogy to 13 C 1/T1 and consistently with a thermal mixing scenario where all the electrons are collectively involved in the dynamic nuclear polarization process and the nuclear spin reservoir is in good thermal contact with the electron spin system.

The aim of this study is to describe the synthesis of, relaxometric characterization of, pharmacokinetic properties of, and animal imaging experiments with a new, low molecular weight gadolinium complex with high binding affinity toward serum albumin. The gadolinium(III) chelate (B25716/1) is based on the structure of the heptadentate ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6 methylperhydro-1,4-diazepine (AAZTA) covalently conjugated to an analogue of deoxycholic acid. The study was conducted as a comparison with that of an analogous complex based on the octadentate diethylenetriaminepentaacetic acid ligand B22956/1 (whose albumin binding properties were previously assessed). The structural modification with respect to B22956/1 leads to a system that can host two coordinated water molecules in fast exchange with bulk water with potential higher efficiency as an MRI contrast agent. On interaction with human serum albumin the expected-field-independent-relaxation enhancement is not observed, possibly as a consequence of the displacement of one of the two inner-sphere water molecules of the gadolinium complex. At clinically relevant magnetic fields, however, the plasma relaxivity of B25716/1 is markedly higher than that shown by B22956/1, owing to concomitant synergistic contributions from the electronic correlation time and water molecules in the second coordination sphere. The capability of B25716/1 to enhance tumor regions in magnetic resonance images was assessed in vivo at 3 T on a xenograft tumor mouse model prepared with PC-3 cells. B25716/1 displays signal enhancements approximately double those observed for B22956/1, in agreement with the findings of the in vitro relaxivity investigations.