Construction Of M6P-HSA-modified Matrine Solid Lipid Nanoparticles And Their Liver-targeted Delivery

Liver fibrosis is a necessary and common pathological change for the progression of various chronic liver diseases.Hepatic stellate cells(HSC)are greatly activated during liver fibrosis and mannose 6 phosphate human serum protein/insulin-like receptor(M6P/IGF ?)are highly expressed on its surface,which can be recognized specifically by mannose 6 phosphate human serum protein(M6P-HSA).Matrine(MT)has a good effect on the prevention and treatment of liver fibrosis,but the systemic distribution and rapid elimination make it difficult to maintain a sufficient therapeutic concentration in liver.Solid lipid nanoparticles(SLN)is a drug delivery system based on lipids with a particle size of 10 nm to 1 ?m,which has the advantages of targeted delivery and controlled drug release.In this study,matrine was used as a model drug,SLN was used as a carrier,and the specific recognition of M6P/IGF ? by M6P-HSA was used to construct matrine loaded solid lipid nanoparticles modified by M6P-HAS(M6P-HSA-MT-SLN),which can target delivery drug to HSC.Targeted delivery capabilities were investigated in terms of pharmacokinetics,tissue distribution,and pharmacodynamics.Construction and evaluation of MT-SLN:The average particle size of MT-SLN prepared by microemulsion probe ultrasonic method is 97.77±3.6 nm,and the average potential is-49.2 ±4.5 mV.TEM image showed that MT-SLN was spherical or ellipsoidal.In vitro release experiments showed that MT-SLN exhibited slow release characteristics.The entrapment efficiency was 61.34+3.42%.The stability test showed that MT-SLN had good stability at 4?.Construction and evaluation of M6P-HSA-MT-SLN:Using p-nitrophenyl ?-d-mannose as raw material,M6P-HSA was coupled to SLN by chemical bond after obtained by phosphorylation,hydrogenation,isothiocyanate esterification.There was no significant difference in particle size,stability and encapsulation efficiency between the M6P-HS A-MT-SLN and MT-SLN.Pharmacokinetics and tissue distribution studies:MT-SLN and M6P-HSA-MT-SLN showed faster plasma clearance and tissue distribution.The liver distributions in liver of M6P-HSA-MT-SLN and MT-SLN were significantly larger than that of MT-solution.The values of TE(%),RTe,CE and RE(72.55%,1.29,2.06 and 1.58)of M6P-HSA-MT-SLN in the liver were larger than those of MT-SLN(66.30%,1.18,1.61 and 1.46),indicating that the liver targeted delivery ability of M6P-HSA-MT-SLN was significantly improved.Pharmacodynamic evaluation:C57 mice were intraperitoneally injected with 30%carbon tetrachloride oil solution combined with drinking 8%ethanol water solution to establish liver fibrosis model.The serum concentration of liver fibrosis markers and HE section staining score were M6P-HSA-MT-SLN<MT-SLN<MT-solution,indicating that the therapeutic effect was M6P-HSA-MT-SLN>MT-SLN>MT-solution,which indicated that M6P-HSA-MT-SLN can effectively increase the therapeutic effect of matrine on liver fibrosis.Conclusion:M6P-HSA-MT-SLN can increase the concentration of matrine in the liver and improve the effect of matrine.The results of this study suggest that SLN modified by M6P-HSA has a good target delivery effect,showing great potential to achieve liver target delivery.