Hydroxypyridinone-Grarted Chitosan Oligosaccharide Nanoparticles As Decorporation Agents For Removal Of Uranium In Vivo

Most of the key radionuclides in the nuclear fuel cycle,such as actinides,possess a combination of 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,very few of them can reduce radiation-induced damage from internal contamination.In this thesis,two kinds of hydroxypyridinone-modified chitosan oligosaccharide nanoparticles(COS-HOPO and COS-HOPO-4)were designed and synthesized aimed at simultaneous removal of uranium and its induced-ROS in vivo.A combination of transmission electron microscope(TEM),elemental analysis(EA),Fourier-transform infrared(FT-IR)spectroscopy and synchrotron radiation X-ray absorption was used to analyze the nanoparticles.The cytotoxicity and uranium removal efficiency of COS-HOPO and COS-HOPO-4 was evaluated by the decorporation assays in vitro and in vivo.Those works are briefly described as follows1)In this work,we synthesized a 3,2-hydroxypyridinone-grafted chitosan oligosaccharide nanoparticle(COS-HOPO)by chemically grafting 3,2-HOPO onto the amine group of COS via an amidation reaction.The transmission electron microscopy(TEM)image was collected,and a mean diameter of 120 nm was calculated for the monodispersed sphere nanoparticles.The HOPO monomer is successfully modified on chitosan as illustrated by the results of FT-IR and elemental analysis.In addition,the results of in vitro adsorption experiments show that the adsorption ratio of Ca2+,Mg2+,Zn2+ and Fe3+ was significantly lower than that of uranium.The cytotoxicity assays indicate that the marriage of chitosan oligosaccharide(COS)and hydroxypyridinone(HOPO)gives rise to a remarkable decrease in toxicity than the HOPO monomer and the commercial DTPA-ZnNa3.The removal efficacy can reach up to 43%and 51%in rat proximal tubular epithelial cells(NRK-52E)by promot and delayed administration,respectively.And the in vivo decorporation efficacy is up to 44%of uranium in the kidneys and 32%in the bones via prophylactic administration.Moreover,the ROS level of the cells treated with COS-HOPO are significantly lower than those of the control group,implying a promising radiation protection effect2)Based on the above results,a new kind of hydroxypyridinone-modified chitosan oligosaccharide nanoparticles COS-HOPO-4 with a mean diameter of 50 nm was designed and synthesized.The comprehensinve cytotoxicity of COS-HOPO-4 was shown much lower than that of HOPO-4 and DTPA-ZnNa3.In addition,COS-HOPO-4 could remove uranium up to 61.7%and 76.2%from cells by promot and delayed administration,respectively.Meanwhile,COS-HOPO-4 also could effectively remove intracellular ROS for the presence of chitosan oligosaccharide.In vivo uranium decorporation assays resulted that 59.5%of uranium could be prevented from transporting into the kidney,and approx 43.6%and 28.6%of uranium could be removed from the kidneys and femurs of mice with delayed administration.In order to explore the decorloration mechnism of COS-HOPO-4,Cy5.5 labeled COS-HOPO-4 was used to study the biodistribution and pharmacokinetics of COS-HOPO-4.Compared with COS-HOPO,the decorporation ability of COS-HOPO-4 was significantly improved due to the higher affinity of tetradentate ligand towards uranyl than the bidentate 3,2-HOPO.