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1.
ACS Sens ; 5(5): 1281-1286, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32352783

RESUMO

Gadolinium-based contrast agents are widely used in magnetic resonance imaging procedures to enhance image contrast. Despite their ubiquitous use in clinical settings, gadolinium is not an innocuous element, as suggested by several disorders associated with its use. Therefore, novel analytical technologies capable of tracking contrast agent excretion through urine are necessary for optimizing patient safety after imaging procedures. Here, we describe an assay to detect and quantify contrast agents in urine based on the luminescence quenching of a metal chelate probe, Eu3+-3,4,3-LI(1,2-HOPO), which only requires 10 min incubation before measurement. Gadolinium-based contrast agents prevent the formation of the Eu3+-3,4,3-LI(1,2-HOPO) complex, subsequently decreasing the luminescence of the assay solution. Three commercial contrast agents, Magnevist, Multihance, and Omniscan, were used to demonstrate the analytical concept in synthetic human urine, and subsequent quantification of mouse urine samples. To the best of our knowledge, this is the first assay capable of detecting and quantifying gadolinium-based contrast agents in urine without sample preparation or digestion.

2.
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
3.
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.

4.
Chem Biol Interact ; 267: 80-88, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27038878

RESUMO

The potential consequences of a major radiological event are not only large-scale external radiation exposure of the population, but also uncontrolled dissemination of, and internal contamination with, radionuclides. When planning an emergency response to radiological and nuclear incidents, one must consider the need for not only post-exposure treatment for contaminated individuals, but also prophylactic measures to protect the workforce facing contaminated areas and patients in the aftermath of such events. In addition to meeting the desired criteria for post-exposure treatments such as safety, ease of administration, and broad-spectrum efficacy against multiple radionuclides and levels of challenge, ideal prophylactic countermeasures must include rapid onset; induce minimal to no performance-decrementing side effects; be compatible with current military Chemical, Biological, Radiological, Nuclear, and Explosive countermeasures; and require minimal logistical burdens. Hydroxypyridinone-based actinide decorporation agents have shown the most promise as decorporation strategies for various radionuclides of concern, including the actinides plutonium and americium. The studies presented here probe the extent of plutonium decorporation efficacy for two chelating agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), from early pre-exposure time points to a delay of up to 7 days in parenteral or oral treatment administration, i.e., well beyond the initial hours of emergency response. Despite delayed treatment after a contamination event, both ligands clearly enhanced plutonium elimination through the investigated 7-day post-treatment period. In addition, a remarkable prophylactic efficacy was revealed for 3,4,3-LI(1,2-HOPO) with treatment as early as 48 h before the plutonium challenge. This work provides new perspectives in the indication and use of experimental actinide decorporation treatments.


Assuntos
Quelantes/química , Descontaminação/métodos , Plutônio/química , Piridonas/química , Amerício/análise , Amerício/química , Animais , Fezes/química , Compostos Heterocíclicos com 1 Anel/química , Camundongos , Plutônio/análise , Plutônio/urina , Fatores de Tempo
5.
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
6.
Chemistry ; 22(15): 5219-32, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-26919627

RESUMO

The synthesis of boron difluoride complexes of a series of curcuminoid derivatives containing various donor end groups is described. Time-dependent (TD)-DFT calculations confirm the charge-transfer character of the second lowest-energy transition band and ascribe the lowest energy band to a "cyanine-like" transition. Photophysical studies reveal that tuning the donor strength of the end groups allows covering a broad spectral range, from the visible to the NIR region, of the UV-visible absorption and fluorescence spectra. Two-photon-excited fluorescence and Z-scan techniques prove that an increase in the donor strength or in the rigidity of the backbone results in a considerable increase in the two-photon cross section, reaching 5000 GM, with predominant two-photon absorption from the S0-S2 charge-transfer transition. Direct comparisons with the hemicurcuminoid derivatives show that the two-photon active band for the curcuminoid derivatives has the same intramolecular charge-transfer character and therefore arises from a dipolar structure. Overall, this structure-relationship study allows the optimization of the two-photon brightness (i.e., 400-900 GM) with one dye that emits in the NIR region of the spectrum. In addition, these dyes demonstrate high intracellular uptake efficiency in Cos7 cells with emission in the visible region, which is further improved by using porous silica nanoparticles as dye vehicles for the imaging of two mammalian carcinoma cells type based on NIR fluorescence emission.


Assuntos
Compostos de Boro/síntese química , Curcumina/química , Curcumina/síntese química , Corantes Fluorescentes/química , Ionóforos/química , Animais , Compostos de Boro/química , Fluorescência , Estrutura Molecular , Processos Fotoquímicos , Fótons , Teoria Quântica , Espectrometria de Fluorescência
7.
Proc Natl Acad Sci U S A ; 112(33): 10342-7, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26240330

RESUMO

Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.


Assuntos
Elementos da Série Actinoide/química , Proteínas de Transporte/química , Proteínas de Transporte/fisiologia , Proteínas/química , Elementos da Série Actinoide/farmacocinética , Quelantes/química , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio , Íons , Cinética , Elementos da Série dos Lantanídeos , Ligantes , Luminescência , Metais/química , Conformação Molecular , Centrais Nucleares , Fotoquímica , Ligação Proteica , Liberação Nociva de Radioativos , Espectrofotometria , Eletricidade Estática , Difração de Raios X
8.
Drug Dev Res ; 76(3): 107-22, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25857483

RESUMO

The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.


Assuntos
Elementos da Série Actinoide/metabolismo , Radioisótopos de Carbono/metabolismo , Piridonas/química , Piridonas/metabolismo , Animais , Radioisótopos de Carbono/química , Quelantes/química , Quelantes/metabolismo , Feminino , Ligantes , Masculino , Taxa de Depuração Metabólica/fisiologia , Camundongos , Piridinas/química , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/fisiologia
9.
Chemistry ; 20(32): 9962-8, 2014 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-25043376

RESUMO

The photophysical properties, solution thermodynamics, and in vivo complex stabilities of Cm(III) complexes formed with multidentate hydroxypyridinonate ligands, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are reported. Both chelators were investigated for their ability to act as antenna chromophores for Cm(III), leading to highly sensitized luminescence emission of the metal upon complexation, with long lifetimes (383 and 196 µs for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), respectively) and remarkable quantum yields (45 % and 16 %, respectively) in aqueous solution. The bright emission peaks were used to probe the electronic structure of the 5f complexes and gain insight into ligand field effects; they were also exploited to determine the high (and proton-independent) stabilities of the corresponding Cm(III) complexes (log ß110 = 21.8(4) for 3,4,3-LI(1,2-HOPO) and log ß120 = 24.5(5) for 5-LIO(Me-3,2-HOPO)). The in vivo complex stability for both ligands was assessed by using (248) Cm as a tracer in a rodent model, which provided a direct comparison with the in vitro thermodynamic results and demonstrated the great potential of 3,4,3-LI(1,2-HOPO) as a therapeutic Cm(III) decontamination agent.


Assuntos
Quelantes/química , Cúrio/química , Substâncias Luminescentes/química , Piridonas/química , Poluentes Radioativos/química , Complexos de Coordenação/química , Cúrio/isolamento & purificação , Descontaminação , Luminescência , Poluentes Radioativos/isolamento & purificação , Termodinâmica
10.
Int J Radiat Biol ; 90(11): 1055-61, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24937372

RESUMO

PURPOSE: To characterize the dose-dependent and sex-related efficacy of the hydroxypyridinonate decorporation agent 3,4,3-LI(1,2-HOPO) at enhancing plutonium elimination when post-exposure treatment is delayed. MATERIALS AND METHODS: Six parenteral dose levels of 3,4,3-LI(1,2-HOPO) from 1-300 µmol/kg were evaluated for decorporating plutonium in female and male Swiss-Webster mice administered a soluble citrate complex of (238)Pu and treated 24 hours later. Necropsies were scheduled at four time-points (2, 4, 8, and 15 days post-contamination) for the female groups and at three time-points (2, 4, and 8 days post-contamination) for the male groups. RESULTS: Elimination enhancement was dose-dependent in the 1-100 µmol/kg dose range at all necropsy time-points, with some significant reductions in full body and tissue content for both female and male animals. The highest dose level resulted in slight toxicity, with a short recovery period, which delayed excretion of the radionuclide. CONCLUSIONS: While differences were noted between the female and male cohorts in efficacy range and recovery times, all groups displayed sustained dose-dependent (238)Pu elimination enhancement after delayed parenteral treatment with 3,4,3-LI(1,2-HOPO), the actinide decorporation agent under development.


Assuntos
Terapia por Quelação/métodos , Compostos Heterocíclicos com 1 Anel/química , Plutônio/efeitos adversos , Piridonas/química , Animais , Carga Corporal (Radioterapia) , Quelantes/química , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos da radiação , Fígado/efeitos da radiação , Masculino , Camundongos , Plutônio/química , Piridonas/uso terapêutico , Fatores Sexuais , Fatores de Tempo
11.
Toxicol Mech Methods ; 23(1): 18-26, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22957518

RESUMO

Because of the continuing use of nuclear fuel sources and heightened threats of nuclear weapon use, the amount of produced and released radionuclides is increasing daily, as is the risk of larger human exposure to fission product actinides. A rodent model was used to follow the in vivo distribution of representative actinides, administered as free metal ions or complexed with chelating agents including diethylenetriamine pentaacetic acid (DTPA) and the hydroxypyridinonate ligands 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). Different metabolic pathways for the different metal ions were evidenced, resulting in intricate ligand- and metal-dependent decorporation mechanisms. While the three studied chelators are known for their unrivaled actinide decorporation efficiency, the corresponding metal complexes may undergo in vivo decomposition and release metal ions in various biological pools. This study sets the basis to further explore the metabolism and in vivo coordination properties of internalized actinides for the future development of viable therapeutic chelating agents.


Assuntos
Elementos da Série Actinoide/farmacocinética , Quelantes/farmacologia , Ácido Pentético/farmacologia , Piridonas/farmacologia , Elementos da Série Actinoide/química , Animais , Quelantes/química , Quelantes/metabolismo , Modelos Animais de Doenças , Feminino , Ligantes , Camundongos , Ácido Pentético/química , Ácido Pentético/metabolismo , Piridonas/química , Piridonas/metabolismo , Distribuição Tecidual
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