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1.
Inorg Chem ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686425

RESUMO

Lanmodulin (LanM) is a recently discovered protein that undergoes a large conformational change in response to rare-earth elements (REEs). Here, we use multiple physicochemical methods to demonstrate that LanM is the most selective macromolecule for REEs characterized to date and even outperforms many synthetic chelators. Moreover, LanM exhibits metal-binding properties and structural stability unseen in most other metalloproteins. LanM retains REE binding down to pH ≈ 2.5, and LanM-REE complexes withstand high temperature (up to 95 °C), repeated acid treatments, and up to molar amounts of competing non-REE metal ions (including Mg, Ca, Zn, and Cu), allowing the protein's use in harsh chemical processes. LanM's unrivaled properties were applied to metal extraction from two distinct REE-containing industrial feedstocks covering a broad range of REE and non-REE concentrations, namely, precombustion coal and electronic waste leachates. After only a single all-aqueous step, quantitative and selective recovery of the REEs from all non-REEs initially present (Li, Na, Mg, Ca, Sr, Al, Si, Mn, Fe, Co, Ni, Cu, Zn, and U) was achieved, demonstrating the universal selectivity of LanM for REEs against non-REEs and its potential application even for industrial low-grade sources, which are currently underutilized. Our work indicates that biosourced macromolecules such as LanM may offer a new paradigm for extractive metallurgy and other applications involving f-elements.

2.
Chem Sci ; 10(28): 6834-6843, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31391906

RESUMO

Current methods for metal chelation are generally based on multidentate organic ligands, which are generated through cumbersome multistep synthetic processes that lack flexibility for systematically varying metal-binding motifs. Octadentate ligands incorporating hydroxypyridinone or catecholamide binding moieties onto a spermine scaffold are known to display some of the highest affinities towards f-elements. Enhancing binding affinity for specific lanthanide or actinide ions however, necessitates ligand architectures that allow for modular and high throughput synthesis. Here we introduce a high-throughput combinatorial library of 16 tetrameric N-substituted glycine oligomers (peptoids) containing hydroxypyridinone or catecholamide chelating units linked via an ethylenediamine bridge and, for comparison, we also synthesized the corresponding mixed ligands derived from the spermine scaffold: 3,4,3-LI(1,2-HOPO)2(CAM)2 and 3,4,3-LI(CAM)2(1,2-HOPO)2. Coordination-based luminescence studies were carried out with Eu3+ and Tb3+ to begin probing the properties of the new ligand architecture and revealed higher sensitization efficiency with the spermine scaffold as well as different spectroscopic features among the structural peptoid isomers. Solution thermodynamic properties of selected ligands revealed different coordination properties between the spermine and peptoid analogues with Eu3+ stability constants log ß 110 ranging from 28.88 ± 3.45 to 43.97 ± 0.49. The general synthetic strategy presented here paves the way for precision design of new specific and versatile ligands, with a variety of applications tailored towards the use of f-elements, including separations, optical device optimization, and pharmaceutical development.

3.
Nat Commun ; 10(1): 2438, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164638

RESUMO

Metal ion separations are critical to numerous fields, including nuclear medicine, waste recycling, space exploration, and fundamental research. Nonetheless, operational conditions and performance are limited, imposing compromises between recovery, purity, and cost. Siderophore-inspired ligands show unprecedented charge-based selectivity and compatibility with harsh industry conditions, affording excellent separation efficiency, robustness and process control. Here, we successfully demonstrate a general separation strategy on three distinct systems, for Ac, Pu, and Bk purification. Separation factors (SF) obtained with model compound 3,4,3-LI(1,2-HOPO) are orders of magnitude higher than with any other ligand currently employed: 106 between Ac and relevant metal impurities, and over 108 for redox-free Pu purification against uranyl ions and trivalent actinides or fission products. Finally, a one-step separation method (SF > 3 × 106 and radiopurity > 99.999%) enables the isolation of Bk from adjacent actinides and fission products. The proposed approach offers a paradigm change for the production of strategic elements.

4.
Dalton Trans ; 48(23): 8238-8247, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31094380

RESUMO

The solution- and solid-state interactions between the octadentate siderophore mimic 3,4,3-LI(1,2-HOPO) (343HOPO) and group IV metal ions were investigated using high-resolution mass spectrometry, liquid chromatography, UV-visible spectrophotometry, metal-competition batch titrations, and single crystal X-ray diffraction. 343HOPO forms a neutral 1 : 1 complex, [HfIV343HOPO], that exhibits extreme stability in aqueous solution, with a log ß110 value reaching 42.3. These results affirm the remarkable charge-based selectivity of 343HOPO for octacoordinated tetravalent cations with a Hf(iv) complex 1021 more stable than its Lu(iii) analogue. Moreover, [HfIV343HOPO] and its Zr(iv) counterpart show exceptional robustness, with the ligand remaining bound to the cation over a very broad pH range: from pH ∼ 11 to acidic conditions as strong as 10 M HCl. In stark contrast, Ti(iv)-343HOPO species are far less stable and undergo hydrolysis at pH as low as ∼6, likely due to the mismatch between the preferred hexacoordinated Ti(iv) ion and octadentate 343HOPO ligand. The extreme charge-based and denticity-driven selectivity of 343HOPO, now observed across the periodic table, paves the way for new selective sequestration systems for radionuclides including medical 44Ti, 89Zr or 177Lu/Hf isotopes, toxic polonium (Po) contaminants, as well as rutherfordium (Rf) research isotopes. Furthermore, despite the lack of a chiral center in 343HOPO, its complexes with metal ions are chiral and appear to form a single set of enantiomers.

5.
Inorg Chem ; 57(22): 14337-14346, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30372069

RESUMO

The solution chemistry of a chelator developed for 227Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven p Ka values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity toward tetravalent metal ions with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL]-, and that of its Eu(III) analogue. Likewise, log ß110 values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL]- and [FeIIIL]2-, respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single crystal X-ray analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the space group P1̅. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. LIII edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and completed after 1 h at room temperature, reinforcing the high suitability of this chelator for 227Th targeted alpha therapy.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Piridonas/química , Compostos Radiofarmacêuticos/química , Tório/química , Anticorpos Monoclonais Humanizados/química , Cinética , Ligantes , Estrutura Molecular , Termodinâmica , Espectroscopia por Absorção de Raios X
6.
Dalton Trans ; 47(21): 7362-7369, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29774904

RESUMO

In order to reveal subtle differences between the solution chemistries of trivalent 4f and 5f elements, the physicochemical and photophysical properties of europium(iii), terbium(iii) and curium(iii) complexes formed with a 7-methoxy-coumarin appended 1,4,7,10-tetraazadodecane-1,4,7-triacid (DO3A) ligand were studied. All three complexes were found to be kinetically inert and exhibit stability constants similar to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) equivalents. The Cm(iii) and Eu(iii) complexes feature strong sensitised emission, while the triplet energy of the coumarin prohibits efficient sensitisation of the Tb(iii) analogue. The data presented here indicate significant differences in perturbation of the sensitising chromophore photophysics between the 4f and 5f elements. In contrast, the size of the metal center appears to not be a determining factor for the physicochemical properties of these kinetically inert Eu(iii), Tb(iii), and Cm(iii) complexes.

7.
Inorg Chem ; 57(9): 5352-5363, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29624372

RESUMO

The hydroxypyridinone ligand 3,4,3-LI(1,2-HOPO) is a promising agent for biological decorporation of radionuclides, and allows spectroscopic detection of many lanthanide (Ln) and actinide (An) species via sensitized luminescence. Despite the manifest uses of this ligand, the structural and thermodynamic properties of its complexes across the An series remain understudied. Theoretical investigations of the binding of An(III) and An(IV) ions, from actinium to einsteinium, by the 3,4,3-LI(1,2-HOPO) ligand, as well as experimental extended X-ray absorption fine structure (EXAFS) studies on the trivalent americium, curium, and californium complexes were employed to address the resulting structures, thermodynamic parameters, redox properties, and corresponding electronic configurations. An(IV) ions were found to form much stronger complexes than An(III) ions, consistent with experimental measurements. Complexation of both An(III) and An(IV) ions generally becomes more favorable for heavier actinides, reflecting increased energy degeneracy driven covalency and concomitant orbital mixing between the 5f orbitals of the An ions and the π orbitals of the ligand. Notably, the ability of this ligand to either accept or donate electron density as needed from its pyridine rings is found to be key to its extraordinary stability across the actinide series.

8.
Sci Rep ; 8(1): 4419, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535330

RESUMO

Several MRI contrast agent clinical formulations are now known to leave deposits of the heavy metal gadolinium in the brain, bones, and other organs of patients. This persistent biological accumulation of gadolinium has been recently recognized as a deleterious outcome in patients administered Gd-based contrast agents (GBCAs) for MRI, prompting the European Medicines Agency to recommend discontinuing the use of over half of the GBCAs currently approved for clinical applications. To address this problem, we find that the orally-available metal decorporation agent 3,4,3-LI(1,2-HOPO) demonstrates superior efficacy at chelating and removing Gd from the body compared to diethylenetriaminepentaacetic acid, a ligand commonly used in the United States in the GBCA Gadopentetate (Magnevist). Using the radiotracer 153Gd to obtain precise biodistribution data, the results herein, supported by speciation simulations, suggest that the prophylactic or post-hoc therapeutic use of 3,4,3-LI(1,2-HOPO) may provide a means to mitigate Gd retention in patients requiring contrast-enhanced MRI.


Assuntos
Gadolínio/metabolismo , Imagem por Ressonância Magnética , Doenças Metabólicas/diagnóstico por imagem , Doenças Metabólicas/metabolismo , Animais , Quelantes/uso terapêutico , Terapia por Quelação/métodos , Meios de Contraste , Modelos Animais de Doenças , Gadolínio/efeitos adversos , Gadolínio/química , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Camundongos , Resultado do Tratamento
9.
Angew Chem Int Ed Engl ; 57(17): 4521-4526, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29473263

RESUMO

The chemistry of trivalent transplutonium ions (Am3+ , Cm3+ , Bk3+ , Cf3+ , Es3+ …) is usually perceived as monotonic and paralleling that of the trivalent lanthanide series. Herein, we present the first extended X-ray absorption fine structure (EXAFS) study performed on a series of aqueous heavy actinide chelates, extending past Cm. The results obtained on diethylenetriaminepentaacetic acid (DTPA) complexes of trivalent Am, Cm, Bk, and Cf show a break to much shorter metal-oxygen nearest-neighbor bond lengths in the case of Cf3+ . Corroborating those results, density functional theory calculations, extended to Es3+ , suggest that the shorter Cf-O and Es-O bonds could arise from the departure of the coordinated water molecule and contraction of the ligand around the metal relative to the other [MIII DTPA(H2 O)]2- (M=Am, Cm, Bk) complexes. Taken together, these experimental and theoretical results demonstrate inhomogeneity within the trivalent transplutonium series that has been insinuated and debated in recent years, and that may also be leveraged for future nuclear waste reprocessing technologies.

10.
Inorg Chem ; 56(21): 12930-12937, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-29019408

RESUMO

Recent efforts to activate the strong uranium-oxygen bonds in the dioxo uranyl cation have been limited to single oxo-group activation through either uranyl reduction and functionalization in solution, or by collision induced dissociation (CID) in the gas-phase, using mass spectrometry (MS). Here, we report and investigate the surprising double activation of uranyl by an organic ligand, 3,4,3-LI(CAM), leading to the formation of a formal U6+ chelate in the gas-phase. The cleavage of both uranyl oxo bonds was experimentally evidenced by CID, using deuterium and 18O isotopic substitutions, and by infrared multiple photon dissociation (IRMPD) spectroscopy. Density functional theory (DFT) computations predict that the overall reaction requires only 132 kJ/mol, with the first oxygen activation entailing about 107 kJ/mol. Combined with analysis of similar, but unreactive ligands, these results shed light on the chelation-driven mechanism of uranyl oxo bond cleavage, demonstrating its dependence on the presence of ligand hydroxyl protons available for direct interactions with the uranyl oxygens.

11.
Nat Chem ; 9(9): 843-849, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28837177

RESUMO

Berkelium (Bk) has been predicted to be the only transplutonium element able to exhibit both +III and +IV oxidation states in solution, but evidence of a stable oxidized Bk chelate has so far remained elusive. Here we describe the stabilization of the heaviest 4+ ion of the periodic table, under mild aqueous conditions, using a siderophore derivative. The resulting Bk(IV) complex exhibits luminescence via sensitization through an intramolecular antenna effect. This neutral Bk(IV) coordination compound is not sequestered by the protein siderocalin-a mammalian metal transporter-in contrast to the negatively charged species obtained with neighbouring trivalent actinides americium, curium and californium (Cf). The corresponding Cf(III)-ligand-protein ternary adduct was characterized by X-ray diffraction analysis. Combined with theoretical predictions, these data add significant insight to the field of transplutonium chemistry, and may lead to innovative Bk separation and purification processes.

12.
Dalton Trans ; 45(48): 19351-19360, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27874897

RESUMO

Solvent extraction of Nb(v) from alkaline aqueous media using quaternary ammonium solutions, especially Aliquat® 336 diluted in an aliphatic diluent, was investigated. The hexaniobate ions (HxNb6O19x-8) were extracted into the organic phase with very high yields at room temperature and within a few minutes, affording easy access to organic solutions of hexaniobates. Several parameters were found to influence the extraction of HxNb6O19x-8 including the nature and concentration of alkali cations, confirming subtle effects previously described for polyoxoniobates such as ion-pairing with alkali ions. The extraction of HxNb6O19x-8 with Aliquat® 336 is also influenced if competing anions are present in the aqueous phase (NO3-, Cl-, C2O42-, SO42- and CO32-) and varies with the pH mainly due to the competitive extraction of hydroxide ions at high pH. The co-extraction of sodium ions with HxNb6O19x-8 was observed as well as the co-extraction of water molecules, suggesting a self-association of the extractant. The proposed liquid-liquid extraction generic system paves the way for innovative niobium (and potentially tantalum) hydrometallurgical processes and it may also afford more direct routes for exploring the chemistry of hexaniobates in organic solvents.

13.
Inorg Chem ; 55(22): 11930-11936, 2016 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-27802058

RESUMO

Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes 225Ac and 227Th are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log ß110 = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the EuIII (a lanthanide surrogate for AcIII), ZrIV, and ThIV complexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with ZrIV and ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound 238PuIV-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Proteínas/química , Radioterapia/métodos , Tório/química , Zircônio/química , Animais , Complexos de Coordenação/farmacocinética , Feminino , Ligantes , Camundongos , Modelos Químicos , Distribuição Tecidual
14.
Nat Chem ; 8(11): 1084, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27768109
15.
Inorg Chem ; 55(12): 5946-56, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27245403

RESUMO

This work determines the potential of solid-state NMR techniques to probe proton, alkali, and niobium environments in Lindqvist salts. Na7HNb6O19·15H2O (1), K8Nb6O19·16H2O (2), and Na8Ta6O19·24.5H2O (3) have been studied by solid-state static and magic angle spinning (MAS) NMR at high and ultrahigh magnetic field (16.4 and 19.9 T). (1)H MAS NMR was found to be a convenient and straightforward tool to discriminate between protonated and nonprotonated clusters AxH8-xM6O19·nH2O (A = alkali ion; M = Nb, Ta). (93)Nb MAS NMR studies at different fields and MAS rotation frequencies have been performed on 1. For the first time, the contributions of NbO5Oµ2H sites were clearly distinguished from those assigned to NbO6 sites in the hexaniobate cluster. The strong broadening of the resonances obtained under MAS was interpreted by combining chemical shift anisotropy (CSA) with quadrupolar effects and by using extensive fitting of the line shapes. In order to obtain the highest accuracy for all NMR parameters (CSA and quadrupolar), (93)Nb WURST QCPMG spectra in the static mode were recorded at 16.4 T for sample 1. The (93)Nb NMR spectra were interpreted in connection with the XRD data available in the literature (i.e., fractional occupancies of the NbO5Oµ2H sites). 1D (23)Na MAS and 2D (23)Na 3QMAS NMR studies of 1 revealed several distinct sodium sites. The multiplicity of the sites was again compared to structural details previously obtained by single-crystal X-ray diffraction (XRD) studies. The (23)Na MAS NMR study of 3 confirmed the presence of a much larger distribution of sodium sites in accordance with the 10 sodium sites predicted by XRD. Finally, the effect of Nb/Ta substitutions in 1 was also probed by multinuclear MAS NMR ((1)H, (23)Na, and (93)Nb).

16.
J Chromatogr A ; 1437: 210-218, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26868447

RESUMO

Tantalum (Ta) and niobium (Nb) are two strategic metals essential to several key sectors, like the aerospace, gas and oil, nuclear and electronic industries, but their separation is really difficult due to their almost identical chemical properties. Whereas they are currently produced by hydrometallurgical processes using fluoride-based solutions, efforts are being made to develop cleaner processes by replacing the fluoride media by alkaline ones. However, methods to analyze Nb and Ta simultaneously in alkaline samples are lacking. In this work, we developed a capillary zone electrophoresis (CE) method able to separate and quantify Nb and Ta directly in alkaline media. This method takes advantage of the hexaniobate and hexatantalate ions which are naturally formed at pH>9 and absorb in the UV domain. First, the detection conditions, the background electrolyte (BGE) pH, the nature of the BGE co-ion and the internal standard (IS) were optimized by a systematic approach. As the BGE counter-ion nature modified the speciation of both ions, sodium- and lithium-based BGE were tested. For each alkaline cation, the BGE ionic strength and separation temperature were optimized using experimental designs. Since changes in the migration order of IS, Nb and Ta were observed within the experimental domain, the resolution was not a monotonic function of ionic strength and separation temperature. This forced us to develop an original data treatment for the prediction of the optimum separation conditions. Depending on the consideration of either peak widths or peak symmetries, with or without additional robustness constraints, four optima were predicted for each tested alkaline cation. The eight predicted optima were tested experimentally and the best experimental optimum was selected considering analysis time, resolution and robustness. The best separation was obtained at 31.0°C and in a BGE containing 10mM LiOH and 35mM LiCH3COO.The separation voltage was finally optimized, resulting in the separation of Nb, Ta, and IS in less than 2.5min, which is three times faster than any CE method ever reported for the separation of Nb and Ta (acidic media included). Some figures of merit of the method were determined such as linearity ranges and limits of quantitation. Finally, the method was successfully applied to the analysis of a real industrial sample.


Assuntos
Técnicas de Química Analítica/métodos , Eletroforese Capilar , Nióbio/análise , Tantálio/análise , Cátions/química , Concentração de Íons de Hidrogênio , Nióbio/química , Nióbio/isolamento & purificação , Tantálio/química , Tantálio/isolamento & purificação , Temperatura
17.
Inorg Chem ; 52(15): 8805-11, 2013 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-23855806

RESUMO

The solution thermodynamics of water-soluble complexes formed between Ce(III), Ce(IV), Th(IV) and the octadentate chelating agent 3,4,3-LI(1,2-HOPO) were investigated. Several techniques including spectrofluorimetric and automated spectrophotometric titrations were used to overcome the slow spontaneous oxidation of Ce(III) complexes yielding to stability constants of log ß110 = 17.4 ± 0.5, log ß11-1 = 8.3 ± 0.4 and log ß111 = 21.2 ± 0.4 for [Ce(III)(3,4,3-LI(1,2-HOPO))](-), [Ce(III)(3,4,3-LI(1,2-HOPO)(OH)](2-), and [Ce(III)(3,4,3-LI(1,2-HOPO)H], respectively. Using the spectral properties of the hydroxypyridinonate chelator in ligand competition titrations against nitrilotriacetic acid, the stability constant log ß110 = 41.5 ± 0.5 was determined for [Ce(IV)(3,4,3-LI(1,2-HOPO))]. Finally, the extraordinarily stable complex [Ce(IV)(3,4,3-LI(1,2-HOPO))] was used in Th(IV) competition titrations, resulting in a stability constant of log ß110 = 40.1 ± 0.5 for [Th(IV)3,4,3-LI(1,2-HOPO))]. These experimental values are in excellent agreement with previous estimates, they are discussed with respect to the ionic radius and oxidation state of each cationic metal, and allow predictions on the stability of other actinide complexes including [U(IV)(3,4,3-LI(1,2-HOPO))], [Np(IV)(3,4,3-LI(1,2-HOPO))], and [Pu(IV)(3,4,3-LI(1,2-HOPO))]. Comparisons with the standard ligand diethylenetriamine pentaacetic acid (DTPA) provide a thermodynamic basis for the observed significantly higher efficacy of 3,4,3-LI(1,2-HOPO) as an in vivo actinide decorporation agent.


Assuntos
Cério/química , Quelantes/química , Compostos Organometálicos/química , Piridonas/química , Tório/química , Estabilidade de Medicamentos , Ligantes , Soluções , Termodinâmica
18.
Metallomics ; 5(6): 619-26, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23446908

RESUMO

Following an internal contamination event, the transport of actinide (An) and lanthanide (Ln) metal ions through the body is facilitated by endogenous ligands such as the human iron-transport protein transferrin (Tf). The recognition of resulting metallo-transferrin complexes (M2Tf) by the cognate transferrin receptor (TfR) is therefore a critical step for cellular uptake of these metal ions. A high performance liquid chromatography-based method has been used to probe the binding of M2Tf with TfR, yielding a direct measurement of the successive thermodynamic constants that correspond to the dissociation of TfR(M2Tf)2 and TfR(M2Tf) complexes for Fe(3+), Ga(3+), La(3+), Nd(3+), Gd(3+), Yb(3+), Lu(3+), (232)Th(4+), (238)UO2(2+), and (242)Pu(4+). Important features of this method are (i) its ability to distinguish both 1 : 1 and 1 : 2 complexes formed between the receptor and the metal-bound transferrin, and (ii) the requirement for very small amounts of each binding partner (<1 nmol of protein per assay). Consistent with previous reports, the strongest receptor affinity is found for Fe2Tf (Kd1 = 5 nM and Kd2 = 20 nM), while the lowest affinity was measured for Pu2Tf (Kd1 = 0.28 µM and Kd2 = 1.8 µM) binding to the TfR. Other toxic metal ions such as Th(IV) and U(VI), when bound to Tf, are well recognized by the TfR. Under the described experimental conditions, the relative stabilities of TfR:(MxTf)y adducts follow the order Fe(3+) >> Th(4+) ~ UO2(2+) ~ Cm(3+) > Ln(3+) ~ Ga(3+) >>> Yb(3+) ~ Pu(4+). This study substantiates a role for Tf in binding lanthanide fission products and actinides, and transporting them into cells by receptor-mediated endocytosis.


Assuntos
Elementos da Série Actinoide/metabolismo , Elementos da Série dos Lantanídeos/metabolismo , Receptores da Transferrina/metabolismo , Transferrina/metabolismo , Elementos da Série Actinoide/química , Transporte Biológico , Cromatografia Líquida de Alta Pressão , Elementos da Série dos Lantanídeos/química , Ligação Proteica , Transferrina/química
19.
J Am Chem Soc ; 135(7): 2676-83, 2013 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-23363005

RESUMO

Worldwide stocks of actinides and lanthanide fission products produced through conventional nuclear spent fuel are increasing continuously, resulting in a growing risk of environmental and human exposure to these toxic radioactive metal ions. Understanding the biomolecular pathways involved in mammalian uptake, transport and storage of these f-elements is crucial to the development of new decontamination strategies and could also be beneficial to the design of new containment and separation processes. To start unraveling these pathways, our approach takes advantage of the unique spectroscopic properties of trivalent curium. We clearly show that the human iron transporter transferrin acts as an antenna that sensitizes curium luminescence through intramolecular energy transfer. This behavior has been used to describe the coordination of curium within the two binding sites of the protein and to investigate the recognition of curium-transferrin complexes by the cognate transferrin receptor. In addition to providing the first protein-curium spectroscopic characterization, these studies prove that transferrin receptor-mediated endocytosis is a viable mechanism of intracellular entry for trivalent actinides such as curium and provide a new tool utilizing the specific luminescence of curium for the determination of other biological actinide transport mechanisms.


Assuntos
Elementos da Série Actinoide/química , Cúrio/química , Transferrina/química , Elementos da Série Actinoide/metabolismo , Cromatografia Líquida de Alta Pressão , Complexos de Coordenação/química , Cúrio/metabolismo , Humanos , Luminescência , Termodinâmica , Transferrina/metabolismo
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