Gallium(III) complexes of DOTA and DOTA-monoamide: kinetic and thermodynamic studies

Given the practical advantages of the (68)Ga isotope in positron emission tomography applications, gallium complexes are gaining increasing importance in biomedical imaging. However, the strong tendency of Ga(3+) to hydrolyze and the slow formation and very high stability of macrocyclic complexes altogether render Ga(3+) coordination chemistry difficult and explain why stability and kinetic data on Ga(3+) complexes are rather scarce. Here we report solution and solid-state studies of Ga(3+) complexes formed with the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, (DOTA)(4-), and its mono(n-butylamide) derivative, (DO3AM(Bu))(3-). Thermodynamic stability constants, log K(GaDOTA) = 26.05 and log K(GaDO3AM(Bu)) = 24.64, were determined by out-of-cell pH-potentiometric titrations. Due to the very slow formation and dissociation of the complexes, equilibration times of up to ～4 weeks were necessary. The kinetics of complex dissociation were followed by (71)Ga NMR under both acidic and alkaline conditions. The GaDOTA complex is significantly more inert (τ(1/2) ～12.2 d at pH = 0 and τ(1/2) ～6.2 h at pH = 10) than the GaDO3AM(Bu) analogue (τ(1/2) ～2.7 d at pH = 0 and τ(1/2) ～0.7 h at pH = 10). Nevertheless, the kinetic inertness of both chelates is extremely high and approves the application of Ga(3+) complexes of such DOTA-like ligands in molecular imaging. The solid-state structure of the GaDOTA complex, crystallized from a strongly acidic solution (pH < 1), evidenced a diprotonated form with protons localized on the free carboxylate pendants.     

Evaluation of minor element concentrations in potatoes using laser-induced breakdown spectroscopy

We have performed spectroscopic analysis of the plasma generated by Nd:YAG laser irradiation of flesh and skin of fresh potatoes. From the spectra recorded with an Echelle spectrometer 11 minor elements have been identified. Their relative concentrations were estimated by comparing the measured spectra to the spectral radiance computed for a plasma in local thermal equilibrium. According the moderate plasma temperature of about 6500 K at the time of spectroscopic observation, the electrons are essentially generated by the ionization of the minor metal atoms, making plasma modeling possible although the organic elements may be out of equilibrium. Among the spectral lines selected for the analysis, the Na I 588.99 and 589.59 nm doublet was found to be partially self-absorbed allowing us to estimate the number density of sodium atoms. The value was found to agree with the number density predicted by the plasma model. As a result, the relative concentrations of the detected minor elements have been estimated for both the flesh and skin of the potatoes. Among these, aluminum and silicon were found to have relatively large mass fractions in the potato skin whereas their presence was not detected in the flesh. The present study shows that laser-induced breakdown spectroscopy is a promising tool to measure the elemental composition of fresh vegetables without any sample preparation.     

Lanthanide(III) Complexes of 4,10‐Bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H6do2a2p) in Solution and in the Solid State: Structural Studies Along the Series

Complexes of 4,10‐bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H₆do2a2p, H₆ L ) with transition metal and lanthanide(III) ions were investigated. The stability constant values of the divalent and trivalent metal‐ion complexes are between the corresponding values of H₄dota and H₈dotp complexes, as a consequence of the ligand basicity. The solid‐state structures of the ligand and of nine lanthanide(III) complexes were determined by X‐ray diffraction. All the complexes are present as twisted‐square‐antiprismatic isomers and their structures can be divided into two series. The first one involves nona‐coordinated complexes of the large lanthanide(III) ions (Ce, Nd, Sm) with a coordinated water molecule. In the series of Sm, Eu, Tb, Dy, Er, Yb, the complexes are octa‐coordinated only by the ligand donor atoms and their coordination cages are more irregular. The formation kinetics and the acid‐assisted dissociation of several Ln^III–H₆ L complexes were investigated at different temperatures and compared with analogous data for complexes of other dota‐like ligands. The [Ce( L )(H₂O)]^3? complex is the most kinetically inert among complexes of the investigated lanthanide(III) ions (Ce, Eu, Gd, Yb). Among mixed phosphonate–acetate dota analogues, kinetic inertness of the cerium(III) complexes is increased with a higher number of phosphonate arms in the ligand, whereas the opposite is true for europium(III) complexes. According to the ¹H NMR spectroscopic pseudo‐contact shifts for the Ce–Eu and Tb–Yb series, the solution structures of the complexes reflect the structures of the [Ce(H L )(H₂O)]^2? and [Yb(H L )]^2? anions, respectively, found in the solid state. However, these solution NMR spectroscopic studies showed that there is no unambiguous relation between ³¹P/¹H lanthanide‐induced shift (LIS) values and coordination of water in the complexes; the values rather express a relative position of the central ions between the N₄ and O₄ planes.     

A Triazacyclononane‐Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric 68Ga Tracers for Positron Emission Tomography

For application in positron emission tomography (PET), PrP9 , a N,N′,N′′‐trisubstituted triazacyclononane with methyl(2‐carboxyethyl)phosphinic acid pendant arms, was developed as ⁶⁸Ga³⁺ complexing agent. The synthesis is short and inexpensive. Ga^III and Fe^III complexes of PrP9 were characterized by single‐crystal X‐ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga^III complex possesses a high thermodynamic stability (log K_[GaL]=26.24) and a high degree of kinetic inertness. ⁶⁸Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO₂‐based ⁶⁸Ge/⁶⁸Ga generator (typically consisting of 0.1 M HCl) can be directly used for labeling purposes. The rate of ⁶⁸Ga activity incorporation at pH 3.3 and 20 °C is higher than for the established chelators DOTA and NOTA. Tris‐amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9 .     

Evaluation of quantum dots applied as switchable layer in a light-controlled electrochemical sensor

Gold electrodes with switchable conductance are created by coating the gold surface with different colloidal quantum dots. For the quantum dot immobilization, a dithiol compound was used. By polarizing the electrode and applying a light pointer, local photocurrents were generated. The performance of this setup was characterized for a variety of different nanoparticle materials regarding drift and signal-to-noise ratio. We varied the following parameters: quantum dot materials and immobilization protocol. The results indicate that the performance of the sensor strongly depends on how the quantum dots are bound to the gold electrode. The best results were obtained by inclusion of an additional polyelectrolyte film, which had been fabricated using layer-by-layer assembly.      

Development and validation of a liquid chromatography–tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study

There is substantial evidence that circulating estrogens promote the proliferation of breast cancer. Consequently, adjuvant hormonal treatment strategies targeting estrogen action have been established. Such hormonal therapies include selective estrogen receptor modulators, such as tamoxifen, which interfere at the estrogen receptors directly, or non-steroidal aromatase inhibitors, such as anastrozole and letrozole, which inhibit estrogen synthesis through blocking the aromatase, a key enzyme of estrogen production. Despite considerable therapeutic success, in several cases, the use of these drugs is limited by side effects that have been described to significantly impair the adherence of patients to endocrine treatment. However, objective data concerning patient adherence and its clinical relevance are limited. One promising approach to check patient-reported adherence is drug monitoring in human plasma. Therefore, a liquid chromatography–tandem mass spectrometry method to determine the plasma concentrations of tamoxifen, anastrozole, and letrozole has been developed and fully validated according to guidelines for clinical and forensic toxicology. The validation criteria evaluated were selectivity, linearity, accuracy and precision, limit of quantification, recovery and matrix effects, sample stability, and carryover. The six-point calibration curves showed linearity over the range of concentrations from 25 to 500 ng/ml for tamoxifen, 5 to 200 ng/ml for anastrozole, and 10 to 300 ng/ml for letrozole. The intra- and inter-day precision and accuracies were always better than 15%. The validated procedure was successfully applied to a clinical study (Patient-Reported Outcomes in Breast Cancer Patients undergoing Endocrine Therapy, PRO-BETh). A major aim of PRO-BETh study is the comprehensive evaluation of adherence to treatment in pre- and post-menopausal women with breast cancer. Plasma samples of 310 breast cancer patients undergoing anti-estrogen therapy were analyzed. Eight samples did not contain a quantifiable amount of drug, strongly indicating non-adherence of the corresponding patients to adjuvant breast cancer treatment. Furthermore, plasma concentrations at the lower end of the observed plasma level distribution might represent a hint but not a confirmation for non-adherence in terms of non-daily and irregular intake of the prescribed drug.     

Picosecond laser ablation of SiO2 layers on silicon substrates

In this work, we report on laser ablation of thermally grown SiO₂ layers from silicon wafer substrates, employing an 8–9 ps laser, at 1064 (IR), 532 (VIS) and 355 nm (UV) wavelengths. High-intensity short-pulse laser radiation allows direct absorption in materials with bandgaps higher than the photon energy. However, our experiments show that in the intensity range of our laser pulses (peak intensities of <2×10¹² W/cm²) the removal of the SiO₂ layer from silicon wafers does not occur by direct absorption in the SiO₂ layer. Instead, we find that the layer is removed by a “lift off” mechanism, actuated by the melting and vaporisation of the absorbing silicon substrate. Furthermore, we find that exceeding the Si melting threshold is not sufficient to remove the SiO₂ layer. A second threshold exists for breaking of the layer caused by sufficient vapour pressure. For SiO₂ layer ablation, we determine layer thickness dependent minimum fluences of 0.7–1.2 J/cm² for IR, 0.1–0.35 J/cm² for VIS and 0.2–0.4 J/cm² for UV wavelength. After correcting the fluences by the reflected laser power, we show that, in contrast to the melting threshold, the threshold for breaking the layer depends on the SiO₂ thickness.     

The Random Phase Property and the Lyapunov Spectrum for Disordered Multi-channel Systems

A random phase property establishing in the weak coupling limit a link between quasi-one-dimensional random Schrödinger operators and full random matrix theory is advocated. Briefly summarized it states that the random transfer matrices placed into a normal system of coordinates act on the isotropic frames and lead to a Markov process with a unique invariant measure which is of geometric nature. On the elliptic part of the transfer matrices, this measure is invariant under the unitaries in the hermitian symplectic group of the universality class under study. While the random phase property can up to now only be proved in special models or in a restricted sense, we provide strong numerical evidence that it holds in the Anderson model of localization. A main outcome of the random phase property is a perturbative calculation of the Lyapunov exponents which shows that the Lyapunov spectrum is equidistant and that the localization lengths for large systems in the unitary, orthogonal and symplectic ensemble differ by a factor 2 each. In an Anderson-Ando model on a tubular geometry with magnetic field and spin-orbit coupling, the normal system of coordinates is calculated and this is used to derive explicit energy dependent formulas for the Lyapunov spectrum.     

Preparation and characterization of microporous fibers for sample preparation and LC‐MS determination of drugs

The aim of this study was the preparation of polypyrrole (PPy) fibers for solid phase microextraction (SPME). PPy coatings were obtained during the electrochemical polymerization process. The utility of various metal wires (Fe, Cu, Ag, Cu/Ag, kanthal and medical stainless steel) as a support for polymers was compared. Various experimental conditions of the synthesis process such as scan rate, voltage limits and number of scans and deposition time were applied. The average polymer thickness was in the range of 7–125 μm and its weight was in the scope of 0.65–5.6 mg. Different techniques, mainly elemental analysis, Fourier transform infrared spectroscopy, microscopy, and chromatography were performed for the characterization of obtained fibers with microporous structure. The extraction efficiency of cardiovascular drugs (metoprolol, propranolol, oxprenolol, propafenone and mexiletine) by means of fibers was tested. The concentration of mentioned compounds in standard solution was in the span of 10–150 ng/mL. LC‐MS was employed for determination of drugs in desorption solution. LODs varied from 0.013 to 1.51 ng/mL for metoprolol and mexiletine respectively. The repeatability of extraction was obtained with the RSD values lower than 10%.