| As an important fuel for the nuclear industry,uranium penetrates into the environment through a variety of ways,entering the human body through inhalation,skin contact and ingestion,causing chemical and radiation damage.As an important drug for the treatment of uranium radiation damage,exhaust promoters can accelerate the excretion of uranium compounds from human body.However,the effects and toxic side effects of the currently approved exhaust promoters need to be further improved,so it is urgent to develop new exhaust promoters to meet the current clinical demand for new exhaust promoters.By screening more than 200 functional adsorbents,researchers found that amidoxime group has strong adsorption and excellent selectivity for uranium in seawater.According to public data,there has been no research report on amidoxime compounds used as discharge promoters.In this paper,small molecules of amidoxime ligand A1～A7 and amidoxime-modified chito-oligosaccharides（ACs）were synthesized,characterized by nuclear magnetic hydrogen and infrared spectroscopy,and their excretion promoting effects were investigated at the in vitro,cellular and animal levels,and quality analysis of compound A6 was conducted.Specific work is as follows:（1）Firstly,amidoxime small molecule compounds A1,A2,A3,A4,A5,A6 and A7 were synthesized by addition reaction,and their structures were verified by nuclear magnetic hydrogen spectroscopy.The uranium expulsion promoting effect of A1～A7 compounds was investigated in the mouse immediate administration experiment.The results showed that compared with the model group,A1～A7 compounds could effectively remove uranium from the mouse body.Among them,the removal capacity of A1,A5 and A6 on uranium in mouse liver and femur was higher than that of Zn Na3-DTPA and DTPA,and the removal capacity of A1 and A6 on uranium in mouse kidney was higher than that of Zn Na3-DTPA and DTPA.A6had the highest removal capacity of uranium in mouse liver,and A1 had the highest removal capacity of uranium in mouse kidney and femur.（2）Secondly,considering that A6 and A1 have the best scavenging ability compared with Zn Na3-DTPA and DTPA in the screening of uranium scavenging ability of liver,kidney and femur in mice,and A6 has a representative structure without the influence of other groups,so the quality control study was conducted on A6.Thin layer chromatography（TLC）,ultraviolet spectrophotometry（UV）and high performance liquid chromatography（HPLC）were used to identify A6 by investigating its physicochemical properties.The results show that the content of inorganic impurities in A6 is less than 0.005%chloride,less than 0.02%sulfate,less than 0.5%drying weight loss,less than 0.2%incandescent residue,less than0.002%heavy metal,less than 0.002%arsenic salt,and the limits of inorganic impurities meet the requirements.A headspace gas chromatographic method was established for determination of residual solvent A6 ethanol with water as solvent and acetonitrile as internal standard.The method was proved to be sensitive,accurate and suitable for the determination of residual solvent in A6.A high performance liquid chromatography method for the determination of A6 content was established.Because A6 has strong polar groups such as hydroxyl group and has large polarity,it is not easy to retain in the commonly used reversed phase C18column,so the hydrophilic chromatographic column KR-60-5CN column was used for analysis.Mobile phase:acetonitrile-20 mmo L/L Na2HPO4（H3PO4adjusted p H to 7.0）（5:95）;Equal degree elution;Flow rate 0.8 m L/min;Column temperature 30℃;Detection wavelength 210 nm;The sample size was 20μL.The results show that the method is simple,specific and accurate,and the separation and symmetry factors meet the requirements of pharmacopoeia.The linear regression equation of A6 is Y=9×107X-81443（r=0.9992）,and the peak area has a good linear relationship with the concentration in the range of 4.0～60μg/m L.（3）Considering that chito-oligosaccharides have excellent biocompatibility,are easy to modify,and can directly act on cells as drug matrix materials,amidoxime group is modified to chito-oligosaccharides through acid-amine condensation reaction,and amidoxime-modified chito-oligosaccharides（ACs）are synthesized,further enhancing the efficacy of amidoxime type release promoters.The structure-activity relationship of oligomer promoters was also studied.The structure of ACs was confirmed by NMR and IR spectra.The morphology and particle size of ACS were investigated by transmission electron microscopy and dynamic light scattering.In vitro expulsion promotion experiments showed that,compared with other essential ions in human body,ACs adsorbed 7.8%of competitive ions at most,but 58.3%of U when the amount of competitive ions was 5 times that of U.In the competition for uranium that has been chelated with HA,although the amount is only 50%of Ha,the amidoxime small molecule AO can compete for 80%of the uranium chelated with Zn Na3-DTPA,which is about 4 times that of Znna3-DTPA.The results of cell expulsion showed that the cell survival rate of Zn Na3-DTPA and small molecules AO decreased to 75%and 60%when the concentration reached 1000mg/L,while that of ACs compounds was close to 90%.ACs compounds remove 80%of the uranium in cells,while Zn Na3-DTPA only removes around35%.The results of animal excretion promotion showed that uranium removal rates of AO and ACs were superior to Zn Na3-DTPA under immediate administration,whether by injection or gavage.The clearance rates of ACs were the highest,reaching 43.6%in kidney and 32.3%in femur.The uranium removal rate of AO was slightly higher than that of ACs during injection administration,but that of ACs was significantly higher than that of AO during intragastric administration.In the case of delayed administration,ACs still reduced uranium content in the body even after 72 h delay.In conclusion,ACs compounds have low toxicity,strong affinity for uranium and high selectivity.Compared with Zn Na3-DTPA,ACS compounds are a more cost-effective uranium emission promoting agent. |
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