H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry.

H4octox, a versatile new octadentate acyclic chelating ligand, has been investigated as an alternative to the acyclic DTPA and the macrocyclic DOTA for trivalent metal ions useful in diagnostic medical imaging or therapeutic applications (Y3+, In3+, La3+, Gd3+, Lu3+). The synthesis of H4octox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y3+, In3+, La3+, Gd3+, and Lu3+ revealed fast chelation and high metal-sequestering capacity. Quantitative labeling with 111In3+ was achieved within 15 min at room temperature at ligand concentrations as low as 10-7 M, exactly the properties required for the development of kit-based radiopharmaceuticals. In vitro serum stability studies and in vivo SPECT imaging confirmed excellent complex stability of [111In(octox)]-. Moreover, it is more lipophilic than most of the multidentate carboxylate- or picolinate-based chelators; it therefore shows more liver clearance and provides a complementary choice in the design of metal-based pharmaceuticals and in the tuning of their pharmacokinetic properties. Finally, H4octox showed a large fluorescence enhancement upon complexation with different metals, in particular, with Y3+ and Lu3+, which could be useful for non-radioactive fluorescent stability and cell studies as well as bimodal imaging. Excellent in vitro stability of [Y(octox)]- against transferrin and Fe3+ was confirmed employing this fluorescence.

Lanthanide near infrared imaging in living cells with Yb3+ nano metal organic frameworks.

We have created unique near-infrared (NIR)-emitting nanoscale metal-organic frameworks (nano-MOFs) incorporating a high density of Yb(3+) lanthanide cations and sensitizers derived from phenylene. We establish here that these nano-MOFs can be incorporated into living cells for NIR imaging. Specifically, we introduce bulk and nano-Yb-phenylenevinylenedicarboxylate-3 (nano-Yb-PVDC-3), a unique MOF based on a PVDC sensitizer-ligand and Yb(3+) NIR-emitting lanthanide cations. This material has been structurally characterized, its stability in various media has been assessed, and its luminescent properties have been studied. We demonstrate that it is stable in certain specific biological media, does not photobleach, and has an IC50 of 100 µg/mL, which is sufficient to allow live cell imaging. Confocal microscopy and inductively coupled plasma measurements reveal that nano-Yb-PVDC-3 can be internalized by cells with a cytoplasmic localization. Despite its relatively low quantum yield, nano-Yb-PVDC-3 emits a sufficient number of photons per unit volume to serve as a NIR-emitting reporter for imaging living HeLa and NIH 3T3 cells. NIR microscopy allows for highly efficient discrimination between the nano-MOF emission signal and the cellular autofluorescence arising from biological material. This work represents a demonstration of the possibility of using NIR lanthanide emission for biological imaging applications in living cells with single-photon excitation.

Efficient Tailoring of Upconversion Selectivity by Engineering Local Structure of Lanthanides in Na(x)REF(3+x) Nanocrystals.

Efficient tailoring of upconversion emissions in lanthanide-doped nanocrystals is of great significance for extended optical applications. Here, we present a facile and highly effective method to tailor the upconversion selectivity by engineering the local structure of lanthanides in Na(x)REF(3+x) nanocrystals. The local structure engineering was achieved through precisely tuning the composition of nanocrystals, with different [Na]/[RE] ([F]/[RE]) ratio. It was found that the lattice parameter as well as the coordination number and local symmetry of lanthanides changed with the composition. A significant difference in the red to green emission ratio, which varied from 1.9 to 71 and 1.6 to 116, was observed for Na(x)YF(3+x):Yb,Er and Na(x)GdF(3+x):Yb,Er nanocrystals, respectively. Moreover, the local structure-dependent upconversion selectivity has been verified for Na(x)YF(3+x):Yb,Tm nanocrystals. In addition, the local structure induced upconversion emission from Er(3+) enhanced 9 times, and the CaF2 shell grown epitaxially over the nanocrystals further promoted the red emission by 450 times, which makes it superior as biomarkers for in vivo bioimaging. These exciting findings in the local structure-dependent upconversion selectivity not only offer a general approach to tailoring lanthanide related upconversion emissions but also benefit multicolor displays and imaging.

In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI.

PURPOSE: A main obstacle to in vivo applications of paramagnetic chemical exchange saturation transfer (paraCEST) is interference from endogenous tissue magnetization transfer contrast (MTC). The suitability of excitation-based frequency labeled exchange transfer (FLEX) to separate out such MTC effects in vivo was tested. METHODS: The FLEX sequence measures modulation of the water signal based on the chemical shift evolution of solute proton magnetization as a function of evolution time. Time-domain analysis of this water signal allows identification of different solute components and provides a mechanism to separate out the rapidly decaying MTC components with short effective transverse relaxation time ( T2*) values. RESULTS: FLEX imaging of paraCEST agents was possible in vitro in phantoms and in vivo in mouse kidneys and bladder. The results demonstrated that FLEX is capable of separating out the MTC signal from tissues in vivo while providing a quantitative exchange rate for the rapidly exchanging paraCEST water protons by fitting the FLEX time-domain signal to FLEX theory. CONCLUSIONS: The first in vivo FLEX images of a paraCEST agent were acquired, which allowed separation of the tissue MTC components. These results show that FLEX imaging has potential for imaging the distribution of functional paraCEST agents in biological tissues.

Bone as target organ for metals: the case of f-elements.

The skeleton is a target organ for most metals. This leads to their bioaccumulation, either as storage of useful oligoelements or as a protection against damage by toxic elements. The different events leading to their accumulation in this organ, under constant remodeling, are not fully understood, nor the full subsequent impact on bone metabolism. This lack of knowledge is particularly true for lanthanides and actinides, whose use has been increasing over recent decades. These metals, known as f-elements, present chemical similarities and differences. After a comparison of the biologically relevant physicochemical properties of lanthanides and actinides, and a brief reminder of the main events of bone metabolism, this review considers the results published over the past decade regarding the interaction between bones and f-elements. Emphasis will be given to the molecular events, which constitute the basis of the most recent toxicological studies in this domain but still need further investigation. Ionic exchanges with the inorganic matrix, interactions with bone proteins, and cellular mechanism disturbances are mainly considered in this review.

Nanoparticle augmented radiation treatment decreases cancer cell proliferation.

We report significant and controlled cell death using novel x-ray-activatable titania nanoparticles (NPs) doped with lanthanides. Preferential incorporation of such materials into tumor tissue can enhance the effect of radiation therapy. Herein, the incorporation of gadolinium into the NPs is designed to optimize localized energy absorption from a conventional medical x-ray. This result is further optimized by the addition of other rare earth elements. Upon irradiation, energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species (ROS). FROM THE CLINICAL EDITOR: The authors report significant and controlled cell death using x-ray-activated titania nanoparticles doped with lanthanides as enhancers. Upon irradiation X-ray energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species.

Ln3+-doped nanoparticles with enhanced NIR-II luminescence for lighting up blood vessels in mice.

Probes functioning in the second near-infrared window (1000-1700 nm, NIR-II) exhibit higher resolution and diminished auto-fluorescence compared to those in the traditional NIR region (700-950 nm). Here, we designed and synthesized rare earth ion doped probes with core/shell/shell structures and bright luminescence in the NIR-II region excited at 808 nm. With the doping of Ce3+ ions, the emission intensity of Er3+ at 1530 nm increased 10 times, while the upconversion luminescence decreased to less than 1%. After being modified with polyacrylic acid and polyethylene glycol, the as-obtained water-soluble probe exhibits continuous high-resolution for distinguishing 0.25 mm blood vessels even 10 h after injection. Noteworthily, the imaging of tumors was achieved by injecting the probe, indicating that the designed NIR-II probe has sufficient brightness and the ability to passively target tumor tissue.

The mechanism of cell uptake for luminescent lanthanide optical probes: the role of macropinocytosis and the effect of enhanced membrane permeability on compartmentalisation.

Inhibition studies and co-localisation experiments with several emissive lanthanide complexes reveal cell uptake by macropinocytosis.

Scandium, yttrium, and lanthanide contents in soil from Serbia and their accumulation in the mushroom Macrolepiota procera (Scop.) Singer.

The mobility (fractionation) of rare earth elements (REEs) and their possible impacts on ecosystems are still relatively unknown. Soil samples were collected from two sites in central Serbia, an unpolluted mountain region (site 1) and a forest near a city (site 2). In order to investigate REE fractions (acid-soluble/exchangeable, reducible, oxidizable, and residual) in soils, BCR sequential extraction was performed. Additionally, the content of REEs was also determined in stipes and caps of the mushroom Macrolepiota procera, growing in the observed sites. Sc, Y, and lanthanide contents were determined by inductively coupled plasma mass spectrometry (ICP-MS), and results were subjected to multivariate data analysis. Application of pattern recognition technique revealed the existence of two distinguished clusters belonging to different geographical sites and determined by greater levels of Sc, Y, and lanthanides in Goc soil compared to Trstenik soil. Additionally, PCA analysis showed that REEs in soil were concentrated in two groups: the first consisted of elements belonging to light REEs and the second contained heavy REEs. These results suggest that the distribution of REEs in soils could indicate the geographical origin and type of soil. The bioconcentration factors and translocation factors for each REE were also calculated. This study provides baseline data on the rare earth element levels in the wild edible mushroom M. procera, growing in Serbia. In terms of bioconcentration and bioexclusion concept, Sc, Y, and REEs were bioexcluded in M. procera for both studied sites.

Paramagnetic liposomes as innovative contrast agents for magnetic resonance (MR) molecular imaging applications.

This article illustrates some innovative applications of liposomes loaded with paramagnetic lanthanide-based complexes in MR molecular imaging field. When a relatively high amount of a Gd(III) chelate is encapsulated in the vesicle, the nanosystem can simultaneously affect both the longitudinal (R(1)) and the transverse (R(2)) relaxation rate of the bulk H2O H-atoms, and this finding can be exploited to design improved thermosensitive liposomes whose MRI response is not longer dependent on the concentration of the probe. The observation that the liposome compartmentalization of a paramagnetic Ln(III) complex induce a significant R(2) enhancement, primarily caused by magnetic susceptibility effects, prompted us to test the potential of such agents in cell-targeting MR experiments. The results obtained indicated that these nanoprobes may have a great potential for the MR visualization of cellular targets (like the glutamine membrane transporters) overexpressing in tumor cells. Liposomes loaded with paramagnetic complexes acting as NMR shift reagents have been recently proposed as highly sensitive CEST MRI agents. The main peculiarity of CEST probes is to allow the MR visualization of different agents present in the same region of interest, and this article provides an illustrative example of the in vivo potential of liposome-based CEST agents.

Supramolecularly Engineered NIR-II and Upconversion Nanoparticles In Vivo Assembly and Disassembly to Improve Bioimaging.

Contrast agents for bioimaging suffer from low accumulation at lesion area and high uptake in the reticuloendothelial system (RES). Assembly of nanoparticles in vivo improves their enrichment at tumors and inflamed areas. However, uncontrollable assembly also occurs at the liver and spleen owing to the uptake of nanoparticles by the RES. This is known to probably cause a higher bioimaging background and more severe health hazards, which may hamper the clinical application. Herein, a new near-infrared (NIR)-controlled supramolecular engineering strategy is developed for in vivo assembly and disassembly between lanthanide upconversion nanoparticles and second near-infrared window (NIR-II, 1000-1700 nm) nanoprobes to realize precision bioimaging of tumors. A supramolecular structure is designed to realize assembly via host-guest interactions of azobenzene and ß-cyclodextrin to enhance the retention of NIR-II nanoprobes in the tumor area. Meanwhile NIR-laser-controllable nanoprobes disassembly brings about a reduction in the bioimaging background as well as acceleration of their RES clearance rate. This strategy may also be used in other nano-to-micro-scale contrast agents to improve bioimaging signal-to-noise ratio and reduce long-term cytotoxicity.

Kinetics-mediate fabrication of multi-model bioimaging lanthanide nanoplates with controllable surface roughness for blood brain barrier transportation.

Effective delivery of imaging agents or therapeutics to the brain has remained elusive due to the poor blood-brain barrier (BBB) permeability, resulting in the apparent risks of inefficient diagnosis and therapeutic agents for brain disease. Herein, we report on the surface roughness mediated BBB transportation for the first time. The lanthanide-based core/shell/shell structured NaYF4:Yb,Er@NaGdF4:Yb@NaNdF4:Yb nanoplates with controllable surface roughness and multi-model bioimaging features were synthesized and used to evaluate the surface roughness dependent BBB permeability without any surface bio-functionalization. By controlling the kinetics of the shell coating process, the hexagon-disc, multi-petals and six-petals nanoplates with different surface roughness can be obtained. Comparing with the NPs with less Ra and receptor-conjugated NPs, the obtained six-petals nanoplates with highest roughness exhibit excellent performance in BBB transportation and tumor targeting, which lay solid foundation for the diagnosis and the therapy of brain tumor.

Selective mineral elements concentration of the intestinal mucosa role of the lysosomes of duodenal enterocytes in the handling of mineral elements after intragastric administration.

Intragastric administration to rats of four soluble lanthanides cerium, lanthanum, europium, thulium and of three soluble elements of group IIIA aluminium, indium and gallium has been shown in previous studies. In this work two new rare earths gadolinium and terbium were studied using the same protocols and the same methods (transmission electron microscopy and ion microanalysis). among the previously studied elements, some of them were administered simultaneously on the one hand aluminium and indium, and on the other hand, lanthanum and cerium. These metals were looked for in intestinal mucosa, liver and kidney. The results showed: a) gadolinium and terbium were selectively concentrated in lysosomes of duodenal enterocytes, precipitated as non-soluble phosphate salts and eliminated with the cell's turn-over in less than 48 hr; b) Administered simultaneously, they precipitated in the same lysosome. c/ none of them was observed in the liver or kidney even with high dose. This study brings up to nine the number of elements forming a non-soluble phosphate salts, explaining their precipitation in lysosomes. None of them have a physiological role, two are toxic (aluminium and indium). This rapid intralysosomal concentration is an efficient mechanism which limits the diffusion of the foreign substances through the digestive barrier, then permits their elimination along with the cytoptose phenomenon in the intestinal lumen.

Application of 1H and 23Na magic angle spinning NMR spectroscopy to define the HRBC up-taking of MRI contrast agents.

The up-take of Gd(III) complexes of BOPTA, DTPA, DOTA, EDTP, HPDO3A, and DOTP in HRBC has been evaluated by measuring the lanthanide induced shift (LIS) produced by the corresponding dysprosium complexes (DC) on the MAS-NMR resonances of water protons and free sodium ions. These complexes are important in their use as MRI contrast agents (MRI-CA) in diagnostics. 1H and 23Na MAS-NMR spectra of HRBC suspension, collected at 9.395T, show only one signal due to extra- and intra-cellular water (or sodium). In MAS spectra, the presence of DC in a cellular compartment produces the LIS of only the nuclei (water proton or sodium) in that cellular compartment and this LIS can be related to the DC concentrations (by the experimental curves of LIS vs. DC concentrations) collected in the physiological solution. To obtain correct results about LIS, the use of MAS technique is mandatory, because it guarantees the only the nuclei staying in the same cellular compartment where the LC is present show the LIS. In all the cases considered, the addition of the DC to HRBC (100% hematocrit) produced a shift of only the extra-cellular water (or sodium) signal and the gradient of concentration (GC) between extra- and intra-cellular compartments resulted greater than 100:1, when calculated by means of sodium signals. These high values of GC are direct proofs that none of the tested dysprosium complexes crosses the HRBC membrane. Since the DC are iso-structural to the gadolinium complexes the corresponding gadolinium ones (MRI-CA) do not cross the HRBC membrane and, consequently, they are not up-taken in HRBC. The GC values calculated by means of water proton signals resulted much lower than those obtained by sodium signals. This proves that the choice of the isotope is a crucial step in order to use this method in the best way. In fact, GC value depends on the lowest detectable LIS which, in turn, depends on the nature of the LC (lanthanide complex) and the observed isotopes.

Lanthanide concentrations in freshwater plants and molluscs, related to those in surface water, pore water and sediment. A case study in The Netherlands.

Industrial emissions of lanthanides to aquatic ecosystems increase, but knowledge of the environmental fate of these metals is limited. Here we focus attention upon the distribution of lanthanides in freshwater ecosystems, describing lanthanide partitioning between sediment, water and biota. Since lanthanides are often used as oxidation-state analogues for actinides, their distribution can reflect long-term behaviour of the radioactive transuranics. Concentrations of all 14 naturally occurring lanthanides were measured by ICP-MS in Sago pondweed (Potamogeton pectinatus), common duckweed (Lemna minor), seven different mollusc species (tissue and shell), two sediment fractions (< 2 mm and < 63 microm), surface water and sediment pore water from five locations in The Netherlands. In all samples, the typical 'saw-tooth' lanthanide pattern was observed, which implies that lanthanides are transported as a coherent group through aquatic ecosystems. Typical deviations from this pattern were found for Ce and Eu and could be explained by their redox chemistry. The variation in concentrations in abiotic fractions was limited, i.e. within one order of magnitude. However, variations of up to three orders of magnitude were observed in biotic samples, suggesting different affinities among organisms for lanthanides as a group, with significant differences only among molluscs and pondweed samples in relation to sampling location. For P. pectinatus it was shown that pore water was the most important lanthanide source, and for snails, food (plants) seems to be the dominant lanthanide source. Lanthanides were not equally distributed between mollusc shell and tissue and the ratio of lanthanide concentrations in shell and tissue were dependent on the sampling location. Shells contained much lower concentrations and were relatively enriched in Eu, and to a lesser extent in Ce. Bioconcentration factors for lanthanides in plants and snails relative to surface water were typically between 10000 and 100000 l x kg(-1) dry matter, while sediment-water partition coefficients were between 100000 and 3000000 l x kg(-1) dry matter. There was a low extent of biomagnification in the plant-to-snail system, with a maximum biomagnification factor of 5.5. Many distribution coefficients displayed a slight decrease with atomic number. This can be attributed to the general increase in ligand stability constants with atomic number, keeping the heavier lanthanides preferentially in solution.

Fixed-bed study for lanthanide (La, Eu, Yb) ions removal from aqueous solutions by immobilized Pseudomonas aeruginosa: experimental data and modelization.

A fixed-bed study was carried out by using cells of Pseudomonas aeruginosa immobilized in polyacrylamide gel as a biosorbent for the removal of lanthanide (La, Eu, Yb) ions from aqueous solutions. The effects of superficial liquid velocity based on empty column, particle size, influent concentration and bed depth on the lanthanum breakthrough curves were investigated. Immobilized biomass effectively removed lanthanum from a 6 mM solution with a maximum adsorption capacity of 342 micromolg(-1) (+/-10%) corresponding closely to that observed in earlier batch studies with free bacterial cells. The Bohart and Adams sorption model was employed to determine characteristic parameters useful for process design. Results indicated that the immobilized cells of P. aeruginosa enable removal of lanthanum, europium and ytterbium ions from aqueous effluents with significant and similar maximum adsorption capacities. Experiments with a mixed cation solution showed that the sequence of preferential biosorption was Eu3+ > or = Yb3+ > La3+. Around 96+/-4% of the bound lanthanum was desorbed from the column and concentrated by eluting with a 0.1 M EDTA solution. The feasibility of regenerating and reusing the biomass through three adsorption/desorption cycles was suggested. Neural networks were used to model breakthrough curves performed in the dynamic process. The ability of this statistical tool to predict the breakthrough times was discussed.

Distribution, speciation, and bioavailability of lanthanides in the Rhine-Meuse estuary, The Netherlands.

Changing environmental conditions may influence the fate and bioavailability of lanthanides (part of the rare earth elements [Ln]) in estuaries. The aim of this study was to quantify the variation in estuarine lanthanide solid/water distribution, speciation, and bioaccumulation. The latter was studied in the amphipod Corophium volutator under field and laboratory conditions. Calculations with the chemical equilibrium model MINEQL+ indicate that dissolved lanthanides are complexed mainly to carbonates and dissolved organic matter. In the water phase, the relative abundance of the free ion, LnCO3, and humic complexes decreases from lanthanum to lutetium, whereas the relative abundance of Ln(CO3)2 increases. Cerium and europium anomalies were found in the water. Europium anomalies were also found in some biota. The biota sediment accumulation factors (BSAFs) decreased across the series from lanthanum to lutetium. Regression analysis revealed that alkalinity correlated negatively with lanthanide uptake. This suggests that increasing complexation reduced bioavailability under the prevailing conditions. The BSAFs did not depend on salinity or pH, which may simplify sediment-quality criteria for fresh versus saline waters. Field BSAFs were significantly lower than laboratory values for the same sediments, which is explained by adaptation of the organisms to lanthanides.

A method for predicting bioavailability of rare earth elements in soils to maize.

A single-extraction procedure using low-molecular-weight organic acids (LMWOAs) as extractant and the first and second steps of a three-step extraction procedure recommended by the European Community Bureau of Reference (BCR; now European Community Standards, Measurement and Testing Programme, Brussels, Belgium) were performed to extract the light rare earth elements (LREEs) La, Ce, Pr, and Nd from wet rhizosphere soil. The extracted soil solutions were successively filtered through membranes with a pore size of less than 0.45 microm and a molecular weight cutoff of less than 1 kDa, which were termed colloidal and truly dissolved fractions, respectively. Apoplastically and symplastically bound LREEs in maize roots were experimentally distinguished by ultrasound-assisted desorption with 1 mM CaCl2 solution at 0 degrees C in ice-cooled water bath. When the LMWOAs extraction method was used, a good correlation was obtained between LREEs in soil colloidal and truly dissolved fractions and LREEs bound to apoplasm and symplasm of maize root. Both apoplastically and symplastically bound LREEs are the result of bioavailability. However, a poor correlation was obtained between LREEs in fractions water soluble, exchangeable and carbonate bound (B1) and Fe-Mn oxide bound (B2) of the BCR method and LREEs in apoplasm and symplasm and in intact roots. Hence, the LMWOAs extraction method is recommended for measuring the bioavailability of LREEs in soils.

A generic biokinetic model for predicting the behaviour of the lanthanide elements in the human body.

Information on the biokinetics of the 15 elements of the lanthanide series, 57La to 71Lu, is too sparse to permit individual development of meaningful biokinetic models to describe the behaviour of each of the elements in humans. The lanthanides show a regular gradation in chemical properties across the series, and animal studies indicate that this is reflected in regular differences in their deposition in tissues such as the liver and skeleton. These regular differences in chemical and biological behaviour have been utilised to construct a generic lanthanide biokinetic model and to define element-specific parameters for each element in the series. This report describes the use of the available biokinetic data for humans and animals to derive the parameters for each of the elements.

Biokinetic data and models for occupational intake of lanthanoids.

PURPOSE: This paper reviews data related to the behavior of the lanthanoid elements (lanthanum through lutetium, atomic numbers 57-71) in the human body and proposes biokinetic models for internally deposited radio-lanthanoids in workers. MATERIALS AND METHODS: Published data on the following topics are reviewed and analyzed: Physico-chemical properties of the lanthanoids as indicators of the potential behavior of these elements in body fluids; the concentrations of the stable lanthanoids in the environment and human body; and results of biokinetic studies of radio-lanthanoids in human subjects and laboratory animals. Respiratory and systemic biokinetic models and gastrointestinal absorption fractions are developed or selected in an effort to represent the typical behavior of lanthanoids in adult humans. RESULTS AND CONCLUSIONS: Generic (element-independent) absorption rates from the respiratory and alimentary tracts to blood and systemic biokinetic models are proposed. The systemic models are largely generic but include some element-specific parameter values to reflect regular changes with ionic radius in certain aspects of the behavior of the lanthanoids, particularly fractional deposition in liver and bone and early removal in urine.