Research Of In Vivo Uranium Decorporation And Radiation Protection Effect Of Polyoxometalates

Uranium is a radioactive element that is widely used as fuels in nuclear power,and its accidental release poses great threat to human beings and the environment.Comprehensive studies show that uranium can enter the body through inhalation,ingestion,and intact or wounded skin in the contaminated zone,and then quickly deposit in the kidneys and bones in the stable form of hexavalent uranium(UO22+).Long-term internal exposure of uranium can lead to irreversible damage to organs,such as renal failure and osteosarcoma.In order to mitigate the internal contamination of uranium,decorporation agents are used to efficiently chelate uranium in vivo and accelerate its excretion.At present,actinide decorporation agents are mainly divided into two categories,one is molecular decorporation agents which is well developed.Diethyltriaminepentaacetic acid(DTPA)salt are certified for actinide decorporation clinically,but its uranium removal effect is extremely limited.A large amounts of actinide decorporation agents has been explored,yet nearly all of them fail to decorporate uranium from bone sufficiently and safely.Recently,a new ligand,5LIO-1-Cm-3,2-HOPO,developed by our group exhibits high uranium removal efficiency from bone,and is therefore considered to be a clinical candidate.Another category is nano-chelators.In the past few years,in order to overcome the disadvantages of fast metabolism and high toxicity of molecular decorporation agents,researchers proposed to use novel nanomaterials for actinides decorporation.More recently,our group developed different types of porous materials(MOF,COF,etc.),such as carboxy-functionalized UiO-66 nanoparticles(UiO-66-(COOH)4-180)and amidoxime(AO)-functionalized CONs(CON-AO),and demonstrated their excellent decorporation performance.However,the study of those materials only focused on the removal of uranium in vivo and overlooked the oxidative stress caused by internal exposure of uranium.A bifunctional sequestering agent(COS-HOPO)consisting of 3,2-HOPO ligand as uranyl binding units and COS as ROS scavengers was designed and displayed effective uranium removal and ROS scavenging ability by our group for the first time.PEG-grafted melanin nanoparticles(MNPs-PEG)that was reported by our group could selectively sequester uranium and thorium in vivo and scavenge ROS induced by the uptake of uranium and thorium by cells.Nevertheless,these nanochelators displayed limited uranium decorporation efficiency and ROS scavenging efficacy,impeding their application in the field of actinide decorporation.In this dissertation,due to the high selectivity for uranyl ions of Polyoxometalates(POMs),especially vacancy-type POMs,and the application of POMs as ROS scavengers used in the treatment of Alzheimer’s disease and other related diseases,we propose to use vacancy-type POMs as a novel material for uranium decorporation and ROS removal purposes,and improved performance was observed.The work is introduced briefly as follows:A trilacunary POM,sodium 9-tungstophosphate(Na9[A-PW9O34]·7H2O,abbreviated PW9),was employed for the following reasons:lacunary POMs with six exposed active oxygen sites satisfy the equatorial coordination mode of uranyl cations;and water-soluble PW9 forms more stable complexes with uranium compared to nanochelators.The results of in vitro adsorption experiments show that PW9 could effectively remove 86.0%of uranyl in the solution in the presence of uranyl ions and excess trace divalent ions(Mg2+、Zn2+、Co2+、Ni2+、Mn2+),while less than 20.0%of the divalent ions was absorbed.Single crystal X-ray diffraction analysis of UO2-PW9 compound shows that two uranyl ions are sandwiched by two trilacunary Keggin-type anions PW9.Subsequently,a series of assays including CCK-8 assay,cell cloning,and erythrocyte hemolysis assay were performed,and the results corrobate that PW9 shows low cytotoxicity and good biocompatibility.Confocal laser scanning microscopy and flow cytometry prove that PW9 can effectively remove excess ROS induced by uranium in cells so that the intracellular ROS is reduced back to the normal level.Finally,the uranium decorporation effect of PW9 was studied by prophylactic administration,prompt administration and delayed administration,and the removal efficiency from kidneys were 74.0%,48.6%,and 37.2%,and 24.4%,19.0%,and 24.4%from bones,respectively,which were significantly higher than that of the clinically used ZnNa3-DTPA.We further synthesized P8W48 via the condensation of four P2W12 for the purpose of optimizing the uranium decorporation and radiation protection performance.The closed cyclic structure of P8W48 contains a central cavity and more oxygen-active sites than PW9,which favors the capture of multiple uranyl ions.The results of in vitro adsorption experiments show that P8W48 could completely remove uranyl in the solution in the presence of uranyl ions and excess trace divalent ions(Mg2+.Zn2+、Co2+、Ni2+、Mn2+),which exhibits better selectivity and binding affinity towards uranyl than PW9.Subsequently,at the cellular level,the viability of NRK-52E cells is dependent on the P8W48 concentration,and the cell survival rate decreased to 54.6%at the P8W48 concentration of 500 μg/mL.Result of flow cytometry prove that P8W48 could effectively remove excess ROS induced by uranium in cells and reduce the intracellular ROS back to the normal level.In vivo uranium decorporation assays indicate that P8W48 could effectively decorporate uranium deposited in the kidneys and bones,especially in the kidneys where the removal efficiency reached 76.0%,obviously better than that of ZnNa3-DTPA,signifying the potential application of POMs in the field of actinides decorporation and radiation protection.