| Acute liver injury(ALI)is a clinical syndrome characterized by severe hepatocyte dysfunction.It has the characteristics of rapid development,short course of disease,high mortality and poor prognosis.At present,ALI has become a major health problem worldwide,and continuous deterioration can even lead to acute liver failure.Therefore,it is of great significance to seek new therapies for the maintenance of acute liver injury and to prevent the deterioration of the disease.Paeoniflorin(PF),as a potential therapeutic agent for liver disease and liver injury,has been shown to have protective effects on many liver diseases through anti-inflammation,anti-oxidation,anti-apoptosis and immunoregulation.However,the oral bioavailability of PF is very low due to liver first pass effect and intestinal P-glycoprotein(P-gp)efflux,which limits its clinical application.In order to better exert the hepatoprotective effect of paeoniflorin,GA-mediated active liver targeting nano-preparations were constructed by using the liver targeting property of glycyrrhetinic acid(GA),thereby improving the tissue distribution and delivery efficiency of PF.The introduction of GA can not only achieve the active targeted delivery of paeoniflorin to the liver,but also inhibit the efflux of P-gp to PF,and further enhance the hepatoprotective effect of PF.Firstly,GA was loaded into alginate zinc nanoscale gel by inverse microemulsion method to prepare glycyrrhetinic acid-zinc alginate nanogels(GA-NGs).In the in vitro release study of GA-NGs,the cumulative release rate of GA molecules was significantly increased when urea was added to the release medium.Since urea is very easy to form hydrogen bonds,it may competitively inhibit the formation of intermolecular hydrogen bonds between GA and sodium alginate.Therefore,it is speculated that GA participates in the construction of zinc alginate nanogels system in the form of hydrogen bonds.Then the GA-NGs optimum process was determined by partial analysis of factorial design and response surface methodology.Glycyrrhetinic acid-mediated paeoniflorin-zinc alginate nanogels(PF/GA-NGs)were prepared by loading paeoniflorin into GA-NGs under the optimal process.At the same time,the characterization of PF/GA-NGs was analyzed,the results showed that PF and GA were encapsulated in zinc alginate nanogels with a particle size of about 70 nm and the morphology was round;the drug loading rates of PF and GA were(5.98±0.20)% and(1.47±0.02)%,respectively,and the drug release curve of paeoniflorin conformed to the first-order kinetic equation.The safety evaluation and in vitro pharmacological activity study showed that PF/GA-NGs had good biological safety and has good anti-inflammatory and antioxidant activity,which can be used for subsequent anti-acute liver injury research.In order to verify the ability of PF/GA-NGs to target the liver,in vivo tissue distribution and cellular uptake experiments were performed.As a result,the fluorescent strength of the liver of the PF/GA-NGs group was 1.49 times higher than that of the PF-NGs group without GA,confirming that GA as a target can make more nanogels aggregate in the liver.Finally,animal experiments were carried out to investigate the effect of PF/GA-NGs on the survival rate of mice with acute liver injury and its pharmacodynamics against acute liver injury.The survival rate curve indicated that PF/GA-NGs could improve the survival rate of mice with acute liver injury.Pharmacodynamic studies have shown that PF/GA-NGs can significantly reduce the levels of ALT,AST,TBIL and GST in the serum of mice with acute liver injury,and exert liver protection.And it can also play an antioxidant role by reducing the level of MDA and increasing the level of SOD.At the same time,it reduced the expression of inflammation and apoptosis-related factors at the transcriptional and protein levels.Therefore,PF/GA-NGs can alleviate the degree of acute liver injury in mice by inhibiting inflammation,reducing oxidative damage and anti-apoptosis.In conclusion,PF/GA-NGs have good biological safety,and can enhance the delivery efficiency of drugs through GA-mediated liver active targeting,thus enhancing the anti-acute liver injury effect of paeoniflorin.The molecular pharmacological mechanisms of the nanogels against liver injury are anti-oxidation,anti-inflammation and anti-apoptosis.PF/GA-NGs not only provides a new therapeutic strategy for the treatment of acute liver injury,but also provides a new way for the clinical application of paeoniflorin and the improvement of its bioavailability. |
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