Hydroxypyridinonate-based Agents For Decorporation And Radiation-protection Of Actinides

The application of actinides has facilitated the development of nuclear energy around the world.In the meantime,incidents of actinide contamination have been the most societal concern mainly due to their dual radio-and chemo-toxicities.Radionuclides such as uranium,thorium,and plutonium may be introduced into the human body by acute exposure or chronic intake,leading to severe tissue damage,cancer,or even death.Till now,the decorporation strategy of metal-ion chelation was considered as the most authorized method.However,the only clinical used actinide chelator,diethylenetriaminepentaacetic acid(DTPA)salts,still suffers from high toxicity and poor uranium decorporation efficiency.Over the years,although extensive research on actinide decontamination have emerged to eliminate the internalized actinides and related toxicity,there are still many challenges in the field of actinides decorporation.(1)Bone is the target organ for actinides,yet most of existing decorporation agents fail to remove them from bone;(2)The internal contamination of actinides usually involves a variety of nuclides,such as U(Ⅵ),Th(Ⅳ),Pu(Ⅳ),Am(Ⅲ),etc.,but the co-decorporation of those nuclides has seldom been reported;(3)The structureefficiency relationship between molecular structure and decorporation efficiency is still unclear;(4)The biostability and bioavailability of decorporation agents need to be improved;(5)Most of existing agents focus on uranium removal in vivo and overlook the oxidative stress caused by radiation,and there has been only a handful of materials reported with the dual functions of decorporation and radiation protection for actinides;(6)The fast excretion and non-targeted distribution of most molecular decorporation ligands strictly restrain their clinical application.Therefore,new decorporation agents with low toxicity and high efficiency is highly demanded for the treatment of actinide contaminated individuals.Hydroxypyridinone(HOPO)ligands are screened out as the optimal ligands for actinides with features of high selectivity,high decorporation efficiency,and low toxicity.5LIO-(Me-3,2-HOPO)and 3,4,3-LI(1,2-HOPO)ligands have been approved for the phase I clinical study in the United States.Therefore,aiming at the challenges of the research field and the great demand for decorporation agents,several new molecular and nanoscale decorporation ligands have been designed and synthesized for decorporation and radiation protection of uranium and thorium.The details are as follows:(1)A decorporation agent which can effectively remove uranium from bone is highly desirable.By introducing an additional methyl onto the N atom of the 3,2-HOPO unit,our group prepared a new Cm-3,2-HOPO based tetradentate ligand,5LIO-1-Cm-3,2-HOPO.In this ligand,the intramolecular hydrogen bond is weakened,leading to increased negative electrostatic potential of oxygen donor and a record high of uranium decorporation efficiency from bones.Following this strategy,we optimized the denticity of Cm-3,2-HOPO units via different linkers and obtained the hexadentate TREN-Cm-3,2-HOPO and octadentate 3,4,3-LI-Cm-3,2-HOPO ligands.In vitro and in vivo assays indicate that the octadentate 3,4,3-LI-Cm-3,2-HOPO shows higher uranium scavenging performance than the hexadentate and tetradentate analogs.Besides,3,4,3-LI-Cm-3,2-HOPO can reduce the uranium concentration in kidney and bone by 84.8%and 51.9%,respectively,which means that the removal efficiency of uranium from bones is further improved compared with the previously reported tetradentate ligand 5-LIO-1-Cm-3,2-HOPO.In addition,we demonstrated for the first time the dual functions of HOPOs in reducing the uranium concentration and alleviating the related oxidative stress.Specifically,we systematically investigated the uranium removal efficacy and protective effect of HOPO ligands,namely bidentate Me-3,2-HOPO,tetradentate 5LIO-1-Cm-3,2-HOPO,and octadentate 3,4,3-LI-Cm-3,2-HOPO.Among these three ligands,the cytotoxicity was decreased gradually with the increase of denticity,and their scavenging ability on various free radicals was determined to follow the order:bidentate<tetradentate<octadentate.Finally,for the NRK-52E cells treated with uranium,both tetradentate 5LIO-1-Cm-3,2HOPO and octadentate 3,4,3-LI-Cm-3,2-HOPO can reduce the intracellular reactive oxygen species(ROS)level to the normal range.Taken together,both in vitro and in vivo assays ensure the superiority of 3,4,3-LI-Cm-3,2-HOPO in actinide decorporation and radiation protection.(2)In most nuclear accidents,the contaminant contains various nuclides including uranium,thorium,and plutonium,leading to internal contamination of multiple nuclides to the victims.However,there are only limited reports of agents to co-decorporate multiple actinides.In this chapter,the cytotoxicity towards AML-12 cells and decorporation efficiency of thorium of three multidentate HOPO ligands including 5-LIO-1-Cm-3,2HOPO,TREN-Cm-3,2-HOPO,and 3,4,3-LI-Cm-3,2-HOPO were investigated.The cytotoxicity assays indicate that both of TREN-Cm-3,2-HOPO and 3,4,3-LI-Cm-3,2-HOPO exhibits low toxicity to the AML-12 cells.In vivo decorporation assays indicated that 3,4,3LI-Cm-3,2-HOPO reach a high record efficiency of thorium in liver and bone by 70.0%and 27.6%,which is the highest among these three ligands.This work demonstrates that the decorporation efficiency of thorium can be improved by increasing the denticity to match the coordination number of thorium.Therefore,the octadentate 3,4,3-LI-Cm-3,2-HOPO shows potential in the broad-spectrum decorporation of U(Ⅵ),Th(Ⅳ),and Pu(Ⅳ).(3)For the design of uranium decorporation agents,toxicity and sequestering efficiency are the two main factors to be considered,and research shows that it is closely related to the connecting linker of tetradentate HOPO ligands.In this chapter,we focused on the optimization of linkers,designed and synthesized two new tetradentate ligands 2LI-Cm-3,2HOPO and 5LIO-CNH-3,2-HOPO that were linked with different backbones.In terms of cytotoxicity,the introduction of carboxyl group in the ligand 2LI-Cm-3,2-HOPO enhances its hydrophilicity,resulting in lower cytotoxicity in comparison to that of 5LIO-1-Cm-3,2HOPO.Subsequently,a new form of linker was optimized to improve the bioavailability by involving a more stable linker of C-N bond instead of amide bond,obtaining a new tetradentate ligand 5LIO-CNH-3,2-HOPO.A series of assays suggest that this ligand maintains low cytotoxicity and high sequestering efficiency at the cellular level,thus possessing bright prospects of the application.(4)Uranium contamination is frequently associated with damages induced by the chemical toxicity of U and consequent oxidative stress.As mentioned above,HOPO ligands can be used as bifunctional decorporation agents,but the synthesis of multidentate ligands is difficult.Besides,the use of bidentate ligands are limited for its high toxicity,low decorporation and radiation protection efficiency.Hence in this work,we developed polyvinyl pyrrolidone-stabilized polydopamine melanin nanoparticles Dpa-PVP by a "onepot" method,and further post-modified the product with a bidentate hydroxypyridone ligand to yield Dpa-PVP-HOPO material.Studies show that Dpa-PVP-HOPO achieves an ultrahigh level of ROS quenching effect due to the synergistic effect of Dpa-PVP and HOPO units.In addition,Dpa-PVP-HOPO shows lower cytotoxicity and better selectivity towards uranyl compared with Dpa-PVP,which can prevent uranium uptake by kidneys and femurs and reduce the amount of acute uranium accumulation.The results show that the combination of Dpa-PVP nanoparticle and HOPO moiety endow the Dpa-PVP-HOPO as an efficient decorporation agent as well as a puissant antioxidant.