Antifungal potential of extracts, fractions and compounds from Uvaria comperei (Annonaceae) and Oxyanthus unilocularis (Rubiaceae).

Phytochemical study of Uvaria comperei afforded an alkaloid, 8,9-dimethoxy-5H-phenanthridin-6-one (1), isolated and characterised (assignment of 1H and 13C NMR) for the first time from a natural source along with two flavonoids, (2S)-5-hydroxy-7,8-dimethoxyflavanone (2) and (2S)-7-hydroxy-5-methoxy-6,8-dimethylflavone (3). Clethric acid (4), oleanoic acid (5), ß-sitosterol 3-O-ß-D-glucopyranoside (9), ß-sitosterol palmitate (6) and a mixture of stigmasterol (7) and ß-sitosterol (8) were isolated from Oxyanthus unilocularis. The structures of these compounds were elucidated using modern spectroscopic techniques including1D and 2D Nuclear Magnetic Resonance (NMR) Spectroscopy (1H, 13C, 1H-1H COSY, HSQC, HMBC) and Mass Spectrometry. Some fractions and compounds from Uvaria comperei exhibited good antifungal activity against clinical isolates and standard strains of yeast species of Candida and Cryptococcus genera while extracts from Oxyanthus unilocularis displayed weak antifungal activity. The results obtained show that Uvaria comperei could be a potential source of antifungal drugs.

Magnetic resonance relaxation induced by superparamagnetic particles used as contrast agents in magnetic resonance imaging: a theoretical review.

Superparamagnetic nanoparticles are used as contrast agents in magnetic resonance imaging and allow, for example, the detection of tumors or the tracking of stem cells in vivo. By producing magnetic inhomogeneities, they influence the nuclear magnetic relaxation times, which results in a darkening, on the image, of the region containing these particles. A great number of studies have been devoted to their magnetic properties, to their synthesis and to their influence on nuclear magnetic relaxation. The theoretical and fundamental understanding of the behavior of these particles is a necessary step in predicting their efficiency as contrast agents, or to be able to experimentally obtain some of their properties from a nuclear magnetic resonance measurement. Many relaxation models have been published, and choosing one of them is not always easy, many parameters and conditions have to be taken into account. Relaxation induced by superparamagnetic particles is generally attributed to an outersphere relaxation mechanism. Each model can only be used under specific conditions (motional averaging regime, static regime, high magnetic field, etc.) or for a particular sequence (Carr-Purcell-Meiboom-Gill, spin echo, free-induction decay, nuclear magnetic relaxation dispersion profile, etc.). The parameters included in the equations must be carefully interpreted. In some more complex conditions, simulations are necessary to be able to predict the relaxation rates. A good agreement is usually observed between the theoretical predictions and the experimental results, although some data still cannot be fully understood, such as the dependence of the transverse relaxation on the magnetic field. WIREs Nanomed Nanobiotechnol 2017, 9:e1468. doi: 10.1002/wnan.1468 For further resources related to this article, please visit the WIREs website.

Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T(2) contrast agent with tunable proton relaxivities.

Monodisperse mesoporous silica (mSiO(2) ) coated superparamagnetic iron oxide (Fe(3) O(4) @mSiO(2) ) nanoparticles (NPs) have been developed as a potential magnetic resonance imaging (MRI) T(2) contrast agent. To evaluate the effect of surface coating on MRI contrast efficiency, we examined the proton relaxivities of Fe(3) O(4) @mSiO(2) NPs with different coating thicknesses. It was found that the mSiO(2) coating has a significant impact on the efficiency of Fe(3) O(4) NPs for MRI contrast enhancement. The efficiency increases with the thickness of mSiO(2) coating and is much higher than that of the commercial contrast agents. Nuclear magnetic resonance (NMR) relaxometry of Fe(3) O(4) @mSiO(2) further revealed that mSiO(2) coating is partially permeable to water molecules and therefore induces the decrease of longitudinal relaxivity, r(1) . Biocompatibility evaluation of various sized (ca. 35-95 nm) Fe(3) O(4) @mSiO(2) NPs was tested on OC-k3 cells and the result showed that these particles have no negative impact on cell viability. The enhanced MRI efficiency of Fe(3) O(4) @mSiO(2) highlights these core-shell particles as highly efficient T(2) contrast agents with high biocompatibility.

In vitro biomedical applications of functionalized iron oxide nanoparticles, including those not related to magnetic properties.

Superparamagnetic iron oxide nanoparticles (SPION) are very promising contrast media, especially for molecular imaging, due to their superior NMR efficacy. They even have wider biomedical applications such as in drug and gene delivery, tissue engineering and bioseparation, or as sensitive biological nanosensors. By coupling them to affinity ligands, SPION can bind to drugs, proteins, enzymes, antibodies or nucleotides. For in vitro biomedical applications, the detection of molecular interaction is possible by using a diversity of systems capable of sensing the magnetic properties of these materials. The goal of the present work was to develop and validate various in vitro biomedical applications of ultrasmall superparamagnetic particles of iron oxide (USPIO), including some that are not related to their magnetic properties. USPIO coated with dextran, starch or bisphosphonate exposing carboxylate groups were synthesized and some of them were functionalized by conjugating various biomolecules, such as biotin, streptavidin and apoptosis, or VCAM-1 specific peptides. The in vitro biomedical applications assessed in the present work included: (1) the relaxometric measurement of antibody concentration, cell receptor expression, molecular interaction, and enzymatic activity in aqueous suspensions; (2) MRI visualization of cells and detection of molecular interaction in an ELISA system; (3) ELISA applications of USPIO derivatives; and (4) detection of specific biomolecules by histochemistry. Our results confirm that rapid and simple in vitro detection of a diversity of functionalized SPION with relevance in medicine is possible by the existing NMR techniques and by chemical staining reactions. The protocols can be applied to minimally prepared biological samples (e.g. whole blood, blood plasma or serum, cell suspensions, biopsies, histological preparations, etc.), and often do not need complicated systems of signal amplification. The use of SPION labeled compounds could furthermore contribute to cost reductions in the diagnosis and in patient care.

Development of magnetic chromatography to sort polydisperse nanoparticles in ferrofluids.

Whatever the strategy of synthesis, nanoparticles in magnetic fluids commonly feature a broad size distribution. However, the presence of several size populations in ferrofluids is often problematic because of the close relationship between the efficiency of the nanoparticles and their physicochemical properties. In this work, a magnetic size sorting procedure is developed in order to reduce this polydispersity, using the magnetic properties of the iron oxide nanoparticles. This magnetic sorting with an adjustable magnetic field allows isolation of the small superparamagnetic particles as well as the larger particles. Magnetometry, nuclear magnetic relaxation dispersion profiles and transmission electron microscopy were successfully used to check the efficiency of the magnetic sorting procedure, which was shown to work as a 'magnetic' chromatography.

Magnetic resonance relaxation properties of superparamagnetic particles.

Nanometric crystals of maghemite are known to exhibit superparamagnetism. Because of the significance of their magnetic moment, maghemite nanoparticles are exceptional contrast agents and are used for magnetic resonance imaging (of the liver, spleen, lymph nodes), for magnetic resonance angiography and for molecular and cellular imaging. The relaxivity of these agents depends on their size, saturation magnetization and magnetic field and also on their degree of clustering. There are different types of maghemite particles whose relaxation characteristics are suited to a specific MRI application. The relaxation induced by maghemite particles is caused by the diffusion of water protons in the inhomogeneous field surrounding the particles. This is well described by a theoretical model that takes magnetite crystal anisotropy and Néel relaxation into account. Another type of superparamagnetic compound is ferritin, the iron-storing protein: it contains a superparamagnetic ferrihydrite core. Even if the resulting magnetic moment of ferritin is far smaller than for magnetite nanoparticles, its massive presence in different organs darkens T(2)-weighted MR images, allowing the noninvasive estimation of iron content, thanks to MRI. The relaxation induced by ferritin in aqueous solutions has been demonstrated to be caused by the exchange of protons between bulk water protons and the surface of the ferrihydrite crystal. However, in vivo, the relaxation properties of ferritin are still unexplained, probably because of protein clustering.

Relaxometric and magnetic characterization of ultrasmall iron oxide nanoparticles with high magnetization. Evaluation as potential T1 magnetic resonance imaging contrast agents for molecular imaging.

Here we report on the synthesis of ultrasmall gamma-Fe2O3 nanoparticles (5 nm) presenting a very narrow particle size distribution and an exceptionally high saturation magnetization. The synthesis has been carried out by decomposition of an iron organometallic precursor in an organic medium. The particles were subsequently stabilized in an aqueous solution at physiological pH, and the colloidal dispersions have been thoroughly characterized by complementary techniques. Particular attention has been given to the assessment of the mean particle size by transmission electron microscopy, X-ray diffraction, dynamic light scattering, magnetic, and relaxometric measurements. The good agreement found between the different techniques points to a very narrow particle size distribution. Regarding the magnetic properties, the particles are superparamagnetic at room temperature and present an unusually high saturation magnetization value. In addition, we describe the potential of these particles as specific positive contrast agents for magnetic resonance molecular imaging.

C-MALISA (cellular magnetic-linked immunosorbent assay), a new application of cellular ELISA for MRI.

A modified cellular ELISA (enzyme-linked immunosorbent assay), named cellular magnetic-linked immunosorbent assay (C-MALISA), has been developed as an application of magnetic resonance imaging (MRI) for in vitro clinical diagnosis. To validate the method, three contrast agents targeted to integrins were synthesized by grafting to USPIO (ultrasmall particles of iron oxide): (a) the CS1 (connecting segment-1) fragment of fibronectin (FN) (USPIO-g-FN); (b) the peptide GRGD (USPIO-g-GRGD); (c) a non-peptidic RGD mimetic (USPIO-g-mimRGD). Jurkat cells and rat mononuclear cells were stimulated to activate their integrins. After cell fixation on ELISA plates, incubation with the contrast agents, rinsing, and digestion in 5N HCl, the samples were analyzed by MRI. Paramagnetic relaxation rate enhancements (delta R2) were measured on images. Delta R2 was converted in values of iron concentration based on a calibration curve. The apparent dissociation constants (K(d)*) of the three contrast agents were estimated based on the MRI measurement of delta R2. K(d)* of 1.22 x 10(-7) M, of 7.00 x 10(-8) M, and of 1.13 x 10(-8) M were found respectively for USPIO-g-FN, USPIO-g-GRGD, and USPIO-g-mimGRG. The MRI confirmed a statistically significant difference (p < 0.01, p < 0.05) between the stimulated cells incubated with integrin-targeted compounds with respect to the controls (i.e., non-stimulated cells and stimulated cells incubated with non-specific USPIO). The integrin specificity of the three compounds was confirmed by the pre-incubation with GRGD (for USPIO-g-mimRGD and USPIO-g-GRGD) or FN (for USPIO-g-FN).

Ferritin-induced relaxation in tissues: an in vitro study.

PURPOSE: To study in vitro the proton relaxation induced in tissues by ferritin, the iron-storing protein of mammals. MATERIALS AND METHODS: Nuclear magnetic relaxation dispersion (NMRD) profiles of liver and spleen from control and iron-overloaded mice are compared with NMRD profiles of ferritin and Fercayl-a ferritin-like akaganeite particle-in aqueous solutions or in 1% agarose gel. RESULTS: The relaxation of water protons induced by ferritin and Fercayl in 1% agarose gel is comparable with the relaxation of aqueous solutions of the same compounds, but slower than the relaxation of liver and spleen. The gel is not a good model of tissues containing ferritin. The longitudinal NMRD profiles of control and iron-overloaded liver and spleen are almost identical: ferritin accumulation has only a slight effect on longitudinal relaxation. The transverse NMRD profiles of liver and spleen tissues are linear, but the slope of the linear regression is larger for iron-loaded organs than for control ones, which is a consequence of a higher ferritin concentration in the former. However, the correlation between the slope of the transverse NMRD profiles and the iron concentration is not very good, probably because transverse relaxation is modified by the clustering of ferritin in cells. CONCLUSION: It could be difficult to develop a general technique for the accurate quantification of ferritin-bound iron by nuclear magnetic resonance or magnetic resonance imaging.

Anomalous nuclear magnetic relaxation of aqueous solutions of ferritin: an unprecedented first-order mechanism.

Ferritin, the iron-storing protein, speeds up proton transverse magnetic relaxation in aqueous solutions. This T(2) shortening is used in MRI to quantify iron in the brain and liver. Current theoretical models underestimate the relaxation enhancement by ferritin at imaging fields, and they do not predict the measured dependence of the rate enhancement on the magnetization of the particles. Here it is shown that a proton exchange dephasing model (PEDM) overcomes these limitations by allowing a first-order relaxation mechanism. The PEDM considers proton exchange between bulk water and exchangeable protons located at the surface of the hydrated iron oxide nanometric core of the protein. Relaxation is shown to depend on the distribution of the frequency shifts of the adsorption sites; the observed properties agree with a Lorentzian distribution. Computer simulations utilizing recent Mössbauer spectroscopy data show that the distribution of these shifts is effectively Lorentzian.

An evaluation of the contributions of diffusion and exchange in relaxation enhancement by MRI contrast agents.

Magnetic compounds are known to enhance water proton relaxation, either by diffusion or by proton exchange. An experimental procedure to distinguish both mechanisms is proposed and validated by relaxation measurements made in water-methanol solutions of Dy(3+), Ni(2+), Gd(3+), Tempo, and AMI-25. The test discriminates according to the character of the transverse relaxation in water-methanol solutions: a mono-exponential decay corresponds to diffusion, while a bi-exponential decay indicates the contribution of a proton exchange. The study of ferritin and akaganeite particle solutions confirms the occurrence of a proton exchange between protons belonging to hydroxyl groups of the particle surface and free water protons.

Cesium adsorption in hydrated iron oxide particles suspensions: an NMR study.

137Cs is an important component of nuclear waste which may pollute water. Its migration in natural environments is slowed down by adsorption on minerals. Cesium adsorption on akaganeite (beta-FeOOH) particles, dextran-coated ferrihydrite (5 Fe(2)O(3)-9H(2)O) particles, and ferritin in aqueous solutions is studied with (133)Cs nuclear magnetic resonance measurements. The longitudinal relaxation time (T(1)) of (133)Cs in the presence of such magnetic particles depends on whether the ions bind to the particle or not. T(1) of (133)Cs ions in aqueous solutions containing the same amount of magnetized particles will not depend on cesium concentration if relaxation is governed by diffusion (when cesium is not able to bind), but it will depend on cesium concentration if exchange governs relaxation (when cesium is able to bind). The method is successfully tested using TEMPO, a nitroxide stable free radical whose relaxation is due to diffusion. (133)Cs relaxation in solutions of ferritin, akaganeite, and dextran-coated ferrihydrite particles is found to result from a cationic exchange of cesium ions between particles surface and bulk ions, owing to adsorption. The effect of pH on (133)Cs relaxation in solutions of the particles is consistent with the adsorption properties of cations on hydrated iron oxides.

Dy-DTPA derivatives as relaxation agents for very high field MRI: the beneficial effect of slow water exchange on the transverse relaxivities.

Proton longitudinal and transverse relaxivities of Dy(DTPA)(2-) and Dy-DTPA bisamide derivatives (Dy(DTPA-BA): Dy-DTPA bisamide, Dy(DTPA-BEA): Dy-DTPA bisethylamide, Dy(DTPA-BnBA): Dy-DTPA bis-n-butylamide, and Dy(DTPA-BBMA): Dy-DTPA bisbismethylamide) were analyzed between 0.47 T and 18.8 T. Curie longitudinal relaxation was clearly observed at magnetic fields larger than 2.4 T, but the longitudinal relaxivities are limited by the fast rotation of the complexes. Rotational correlation times were separately assessed by deuterium relaxometry of the diamagnetic deuterated lanthanum analogs. Transverse relaxivity, which depends on the square of the magnetic field and on the residence time of the coordinated water molecule (tau(M)), was more than 7.5 times larger at 18.8 T and 310 K for Dy(DTPA-BA) and Dy(DTPA-BEA) as compared to Dy(DTPA)(2-). This difference is mainly related to the slower water exchange of the bisamide complexes, as confirmed by the values of tau(M) measured by oxygen-17 relaxometry. Such Dy-complexes, characterized by relatively long tau(M) values (tauM310 larger than 100 ns but smaller than 1 micros), thus appear to be useful as negative T(2) (or transverse) contrast agents for high-field imaging. This was demonstrated by the spin-echo images of phantoms obtained at 4.7 T on samples containing Dy(DTPA)(2-) and Dy(DTPA-BEA).