RESUMO
The chemical toxicity and the oxidative stress induced by the internal exposure of uranium is responsible for the long-term adverse effect of in vivo contamination of uranium. An agent with simultaneous removal capability of uranium and excess reactive oxygen species (ROS) is highly desired. Herein, the lacunary Keggin-type polyoxometalate (POM) is demonstrated to selectively bind with uranyl ions in the presence of excess essential divalent ions and exhibits a compelling ROS scavenging efficiency of 78.8%. In vivo uranium decorporation assays illustrate the uranium sequestration efficiencies of 74.0%, 49.4%, and 37.1% from kidneys by prophylactic, prompt, and delayed administration of lacunary POM solution, respectively. The superior ROS quenching and uranium removal performance in comparison with all reported bifunctional agents endow lacunary polyoxometalates as novel agents to effectively protect people from injuries caused by the internal exposure of actinides.
Assuntos
Urânio , Humanos , Urânio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rim/metabolismo , Íons/metabolismoRESUMO
With the extensive usage of gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI), gadolinium deposition has been observed in the brain, kidneys, liver, etc., and this is also closely related to the development of nephrogenic systemic fibrosis (NSF) in patients with renal dysfunction. Chelation, thereby promoting the elimination of deposited Gd(III), seems to be promising for alleviating these problems. Despite many ligands suitable for chelation therapy having been studied, the decorporation of transition metals (e.g. iron, copper, lead, etc.) and actinides (e.g. uranium, plutonium, etc.) has long been a primary concern, whereas the study of Gd(III) has been extremely limited. Due to their excellent metal binding abilities in vivo and therapeutic effects toward neurodegenerative diseases, bidentate hydroxypyridinone ligands are expected to be able to remove Gd(III) from the brain, kidneys, bones, and liver. Herein, the Gd(III) decorporation efficacy of a bidentate hydroxypyridinone ligand (Me-3,2-HOPO) has been evaluated. The complexation behavior between Me-3,2-HOPO and Gd(III) in solution and solid states was characterized with the assistance of potentiometric titration and X-ray diffraction techniques, respectively. Solution-based thermodynamic studies illustrate that the dominant species of complex between Gd(III) and Me-3,2-HOPO (HL) is GdL2+ (log ß120 = 11.8 (3)) at pH 7.4. The structure of the Gd-Me-3,2-HOPO crystal obtained from a room temperature reaction reveals the formation of a Gd(III) dimer that is chelated by four ligands as a result of metal ion hydration and ligand complexation. Cellular Gd(III) removal assays illustrate that Me-3,2-HOPO could effectively reduce final amounts of gadolinium by 77.6% and 66.1% from rat renal proximal tubular epithelial (NRK-52E) cells and alpha mouse liver 12 (AML-12) cells, respectively. Our current results suggest the potential of bidentate HOPO ligands as an effective approach to treat patients suffering from Gd(III) toxicity.
Assuntos
Gadolínio , Piridonas , Animais , Quelantes/química , Meios de Contraste/química , Gadolínio/química , Ligantes , Camundongos , Piridonas/química , RatosRESUMO
An agent for actinide sequestration with fast uranium uptake kinetics and efficient inâ vivo uranium removal using a nanoscale metal-organic framework (nano-MOF) is proposed. UiO-66 nanoparticles post-synthetically functionalized with carboxyl groups, UiO-66-(COOH)4 -180, exhibit the fastest uranium uptake kinetics reported with more than 65 % of uranyl in fetal bovine serum (FBS) removed within 5â min. Moreover, the inâ vivo bio-distribution studies show that the material partially accumulates in kidneys and femurs where uranium mainly deposits facilitating the inâ vivo sequestration of uranium. The results of the inâ vivo uranium decorporation assays with mice show that UiO-66-(COOH)4 -180 could successfully reduce the amounts of uranyl deposited in kidneys and femurs by up to 55.4 % and 36.5 %, respectively, and is significantly more efficient than the commercial actinide decorporation agent, ZnNa3 -DTPA.
Assuntos
Estruturas Metalorgânicas/química , Nanopartículas/química , Urânio/química , Animais , BovinosRESUMO
Searching for actinide decorporation agents with advantages of high decorporation efficiency, minimal biological toxicity, and high oral efficiency is crucial for nuclear safety and the sustainable development of nuclear energy. Removing actinides deposited in bones after intake is one of the most significant challenges remaining in this field because of the instantaneous formation of highly stable actinide phosphate complexes upon contact with hydroxyapatite. Here we report a hydroxypyridinone-based ligand (5LIO-1-Cm-3,2-HOPO) exhibiting stronger affinity for U(VI) compared with the reported tetradentate hydroxypyridinone ligands. This is further revealed by the first principles calculation analysis on bonding between the ligand and uranium. Both in vitro uranium removal assay and in vivo decorporation experiments with mice show that 5LIO-1-Cm-3,2-HOPO can remove uranium from kidneys and bones with high efficiencies, while the decorporation efficiency is nearly independent of the treatment time. Moreover, this ligand shows a high oral decorporation efficiency, making it attractive for practical applications.
Assuntos
Osso e Ossos/química , Quelantes/administração & dosagem , Piridonas/administração & dosagem , Lesões por Radiação/terapia , Urânio/toxicidade , Adsorção , Animais , Osso e Ossos/metabolismo , Quelantes/química , Feminino , Humanos , Rim/química , Rim/metabolismo , Ligantes , Camundongos , Piridonas/química , Lesões por Radiação/induzido quimicamente , Lesões por Radiação/metabolismo , Urânio/química , Urânio/metabolismoRESUMO
Uranium poses a threat for severe renal and bone damage in vivo. With the rapid development of nuclear industry, it is more urgent than ever to search for potential in vivo uranium chelators. In this work, 3-hydroxy-2-pyrrolidinone (HPD) is investigated as a new potential uranium decorporation ligand. The potentiometric titration measurements were carried out, and the stability constants were determined to be log ß110 = 10.5(7), log ß120 = 20.7(9), and log ß130 = 28.2(4). The species distribution diagram shows that nearly all uranyl is complexed by HPD at pH 7.4 under the defined condition. A single crystal of uranyl and HPD complexes, [(UO2)3O(H2O)3(C4H6NO2)3]·NO3·12H2O (uranyl-HPD), was obtained via an evaporation method. The overall structure of uranyl-HPD is a trimer that consists of three uranyl units and three HPD ligands. The uranyl unit is equatorially coordinated by three oxygen atoms from two HPD agents, one coordinated water molecule, and one µ3-O atom that is shared by three uranyl units. The results of the cytotoxicity assay indicate that the ligand is less toxic than the chelators used clinically (i.e., DTPA-ZnNa3 and 3-hydroxy-1,2-dimethyl-4(1 H)-pyridone (DFP)). The results of the uranium removal assay using the NRK-52E cell show that it could reduce as much as 58% of the uranium content at the cellular level. Furthermore, the in vivo uranium decorporation assays demonstrate that HPD can remove 52% of uranium deposited in the kidney but shows poor uranium removal efficacy in the bone.
Assuntos
Quelantes/farmacologia , Pirrolidinonas/farmacologia , Termodinâmica , Urânio/isolamento & purificação , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Ligantes , Estrutura Molecular , Pirrolidinonas/química , Ratos , Soluções , Urânio/químicaRESUMO
Most of the key radionuclides in the nuclear fuel cycle, such as actinides, possess a combination of heavy metal chemotoxicity and radiotoxicity and therefore represent a severe threat to the ecological environment and public safety. The radiotoxicity originates from direct radiation-induced organ damage and indirect damage, mostly through radiation-induced reactive oxygen species (ROS). Although effective chelating agents that can accelerate the excretion of actinides, such as uranium, have been developed in the past several decades, very few of them can reduce radiation-induced damage from internal contamination. In fact, the strategy of simultaneous removal of actinides and their induced-ROS in vivo has scarcely been considered. Here, we report a 3,2-hydroxypyridinone-grafted chitosan oligosaccharide nanoparticle (COS-HOPO) as a new type of decorporation agent that is effective for the removal of both uranium and ROS in vivo. The cytotoxicity and decorporation assays indicate that the marriage of chitosan oligosaccharide (COS) and hydroxypyridinone (HOPO) gives rise to a remarkable decrease in toxicity and promotion of the uranium removal capability from both kidneys and femurs. The decorporation efficacy can reach up to 43% in rat proximal tubular epithelial cells (NRK-52E), 44% in kidneys, and 32% in femurs. Moreover, the ROS levels of the cells treated with COS-HOPO are significantly lower than those of the control group, implying a promising radiation protection effect. The detoxification mechanism of COS-HOPO is closely related to both chelating U(VI)- and scavenging U(VI)-induced intracellular ROS.