Research On The Druggability Of A Novel 3,2-Hydroxypyridonebased Chelating Decorporation Agent

Uranium is widely used due to the development of nuclear technology in energy,military and so on,but in the event of a leakage which can enter the human’s body causing internal uranium contamination and posing a serious threat to practitioners and public health.The most effective way to removal uranium from the body is chelation therapy which uses a decorporation agent to bind efficiently with uranium to reduce the accumulation in vivo and accelerate excretion.However,research on decorporation agents have been very slow,and two approved chelators by FDA are aminocarboxylic acids developed in the 1950s,which are virtually ineffective on chelating uranium.The novel 3,2-hydroxypyridone-based chelator 5LIO-1-Cm-3,2-HOPO can be orally administered and effectively pro-mote the excretion of uranium from tissues and organs with slight toxicity and no timeli-ness,especially reducing 90%of uranium accumulation in kidney and 50%in bone.5LIO-1-Cm-3,2-HOPO is the best compound reported so far to removal uranium from the body,showing potential druggability.Research on 5LIO-1-Cm-3,2-HOPO is still in its infancy,and it is of great significance to carry out systematic druggability.The main contents of this research are as follows:1.The equilibrium solubility of 5LIO-1-Cm-3,2-HOPO in different solvents was deter-mined by high performance liquid chromatography.Using the shake flask method to measure the apparent lipid-water partition coefficient in water and different p H solutions.The dissociation constant was analyzed by potentiometric titration and the stability was investigated in different media.The results show that the equilibrium solubility of 5LIO-1-Cm-3,2-HOPO was in the range of 50～2500μg/m L,log D was between-1～-0.5,p K_a1 and p K_a2 were 8.53±0.07 and 9.14±0.08,respectively,and the stability was good under various influencing factors.In conclusion,5LIO-1-Cm-3,2-HOPO is a low solubil-ity and hydrophilic molecular drug with weak acidity and stable chemical properties.Given the limited solubility of the compound,there is still suboptimal absorption.2.A method for the quantitative analysis of 5LIO-1-Cm-3,2-HOPO in biological samples was established and methodologically validated.The method has a lower limit of quanti-fication of 50 ng/m L,a linear range of 50～10000 ng/m L,possessing good selectivity,no residue,biological matrix does not interfere with the determination.It can be used for the exclusive and sensitive determination of 5LIO-1-Cm-3,2-HOPO in plasma,urine,feces and tissue samples,and has been successfully applied in the pharmacokinetic study of5LIO-1-Cm-3,2-HOPO.3.The pharmacokinetics of 5LIO-1-Cm-3,2-HOPO given intravenously（10 mg/kg）or single dose orally（260 mg/kg）in rats were investigated.After intravenous administration of 5LIO-1-Cm-3,2-HOPO（10 mg/kg）in rats,the elim-ination was rapid in vivo,with an t_1/2 of 0.94 h,the drug concentration in plasma was at the lower limit of quantification level after administration 6 hours.Rats given intrave-nously 5LIO-1-Cm-3,2-HOPO 96 hours later,the cumulative excretion of 5LIO-1-Cm-3,2-HOPO in urine and feces were 908.21μg and 5.48μg,accounting for 44.6%and 0.27%of the administered dose respectively,and about 45%of the drug was excreted in the urine as prototype form after intravenous injection.After intravenous injection of 5LIO-1-Cm-3,2-HOPO,the drug was distributed in all tissues and no accumulation was found and it was mainly distributed in the kidney and intestine.After single dose oral administration,the drug was rapidly absorbed into the blood by the gastrointestinal tract,and the maximum blood concentration of 215 ng/m L was reached at 1.56 hours.The drug concentration in plasma was at the lower limit of quantification after 10 hours.The AUC_（0-∞）was 11018 h*ng/m L,and the bioavailability in rats after a single oral administration was 4.39%.The cumulative excretion of 5LIO-1-Cm-3,2-HOPO in urine and feces were 216.71μg and 5695.16μg,accounting for 0.41%and10.65%of the administered dose respectively,and about 11%of the drug was excreted in the feces as prototype form.The drug was distributed in all tissues after single dose oral administration,and no accumulation was found with the highest drug concentrations in the stomach and intestine.4.The acute toxicity of 5LIO-1-Cm-3,2-HOPO was clarified after mice were given5LIO-1-Cm-3,2-HOPO in a single dose oral administration at 500 mg/kg,1000 mg/kg and 2000 mg/kg.All mice survived until the end of the experiment,and no abnormalities were observed in the skin,eyes,ears,nose and mouth.Further observing the organs of each mouse after dissection did not reveal any damaging effect on the organs.All animals showed stable body weight growth at the end of the 14 days observation period,compared with the control group,there was no statistical difference in the body weight of mice given different doses,and no effect of 5LIO-1-Cm-3,2-HOPO on the growth of mice was ob-served.In summary,this paper presents the first systematic druggability study of the decorpora-tion agent 5LIO-1-Cm-3,2-HOPO.The physicochemical properties,pharmacokinetic dis-posal rules and acute toxicity experiments show that the compound has stable chemical properties,can be absorbed into the blood by the gastrointestinal tract,has no accumula-tion in various tissues and organs and has a good safety.Combined with the high decor-poration efficiency of oral administration,it showed that the compound possess good druggability.Considering the limited solubility of 5LIO-1-Cm-3,2-HOPO and the possibility of adhesion by the gastrointestinal tract or further metabolic transformation,resulting in low bioavailability,and the absorption of 5LIO-1-Cm-3,2-HOPO in the gas-trointestinal tract can be improved by using formulation technologies such as liposomes and nanoparticles,so that its efficacy is not limited by the absorption in vivo.This study not only provides data support for the prediction of the druggability of 5LIO-1-Cm-3,2-HOPO,but also promotes the compound to enter into the preclinical research,and also supplies a meaningful reference for the future evaluation of the druggability properties of other chelating decorporation agents,accelerating the development of new high efficiency and low toxicity decorporation agents.