Pharmacokinetic Study Of JK-102 In Lipid Nanoparticle Of MRNA Vaccine

Since the outbreak of COVID-19 in 2020,the cumulative number of confirmed cases worldwide has exceeded 450 million,and it is a major threat to global public health.The development of vaccines to prevent COVID-19 infection has become a top priority for governments and vaccine manufacturers.Today,the officially approved COVID-19 vaccines include mRNA-1273 produced by Moderna,which is approved by the FDA.mRNA-1273 is a nucleic acid vaccine delivered by a lipid nanoparticle(LNP).LNP has become a popular delivery system as mRNA vaccines are widely used to vaccinate the public.Among the four components of LNP,the most important is ionizable cationic lipid,because it can directly affect the efficiency of mRNA delivery and transfection.Judging from the clinical trial data,the proportion of adverse reactions after the injection of mRNA-1273 is much higher than that of other influenza vaccines.After analyzing the main components of the mRNA-1273 vaccine,it was speculated that the toxic and side effects of the Moderna vaccine may come from the ionizable cationic lipid SM-102 in the mRNA-1273 vaccine LNP.JK-102,chemical name is heptadecan-9-yl(7-((2-hydroxyethyl)(5-(((undecyloxy)carbonyl)oxy)hexyl)amino)octyl)carbonate,is a new type of ionizable cationic lipid obtained by transforming the carboxylate structure in SM-102 into carbonate ester.It is designed to improve the rate of removal of ionizable cationic lipids from plasma and tissues,reduce the toxicity of LNP delivery systems to mRNA vaccines,and reduce the incidence of adverse reactions.Since JK-102 is a new type of ionizable cationic lipid,the absolute quantitative analysis method of JK-102 has not been established at this stage.Therefore,in this study,the quantitative analysis method for JK-102 in rats based on LC-MS/MS technology was established for the first time,and then the non-clinical pharmacokinetic study of JK-102 was conducted.In this study,rats were used as animal models,and a quantitative analysis method of JK-102 in rat plasma was established.After the analysis method was confirmed,the pharmacokinetics of JK-102 in rat plasma was evaluated.The results showed that:after intramuscular injection of JK-102 in rats,the T_maxwas 10±1.265 h,and the absorption in vivo was slow.t_1/2was 3.787±0.804 h and CL was 28.696±7.485L/h/kg,indicating that JK-102 was eliminated slowly in vivo,and the larger Vd value indicates that there may be tissue accumulation.Then this subject studied the tissue distribution of JK-102 in rats.The results showed that the concentration of JK-102 in the liver and spleen was lower than that of LLOQ,but the concentration in muscle tissue was higher after 5 days of administration.The main reason may be that the metabolism rate of JK-102 in the liver and spleen is faster,and it exists in the liver in the form of metabolites,indicating that the structural modification of JK-102improves the metabolism rate in the liver and spleen.The higher concentration in muscle tissue indicated that after intramuscular injection of JK-102,the elimination of JK-102 in rat muscle was slow,and there was a certain degree of muscle accumulation.Finally,this subject established a quantitative analysis method for JK-102 in rat urine and feces,and determined the concentration of JK-102 in urine and feces collected by rats at various time periods between 0 and 120 h after intramuscular injection.The results showed that:after intramuscular injection in rats,JK-102 in rats was not excreted in urine and feces in the form of prototype in various time periods,which confirmed that JK-102 was metabolized by esterase in the liver.Speculation of the corresponding metabolites.In the end,the possible metabolites of JK-102 were preliminarily speculated.In summary,the non-clinical pharmacokinetic study of JK-102 was conducted in this study,providing technical support for scientific design of LNP carrier materials and safety evaluation.