Preparation And Evaluation Of Phosphorylated Lamivudine-Conjugated Chitosan As Targeted Anti-HBV Prodrug

Hepatitis B is a global infectious disease that is known as the most common infectious disease with AIDS and tuberculosis.Studies have shown that about one in ten Chinese people are hepatitis B virus(HBV)carriers.Lamivudine(3TC),a modern anti-hepatitis B virus nucleoside drug,is limited in its clinical applications due to its non-specific biodistribution and side effects on normal cells.Chitosan(CS)is a product of chitin deacetylation,as a natural macromolecule material with good biocompatibility,chitosan and its derivatives have been extensively studied and applied to drug delivery system.Lactose(LA),as a multifunctional polyhydroxy acid has good affinity for the organism,can specifically recognize the asialoglycoprotein receptor on the surface of liver cells.In this study,chitosan was used as the backbone to connect 3TC through the arm of O-isopropyl hydroophosphite,and lactose was used to modify the chitosan to improve the water solubility and targeting of the drug system.CS-3TC and LA-CS-3TC were synthesized respectively.The obtained polymers were characterized by XRD,SEM,NMR and other methods.CS-3TC and LA-CS-3TC showed fibrous and similar hydrogel morphology under SEM,respectively.The polymer system was labeled by linking fluorescein isothiocyanate with the amino groups of chitosan,and the in vitro dissolution,toxicity and activity were detected.The experimental results show that the solubility of CS-3TC is 17.074 g·L-1 and LS-CS-3TC is increased to 227.207 g·L-1.Fluorescence experiments showed that more than 90%of the cells were administered by the drug,indicating that the synthetic drug delivery system was able to target the release of 3TC-isopropyl monophosphate,which was more rapidly acting in the reverse transcription process of the virusrelative.Also,the release of the assay at pH=1.1 and pH=7.4 showed that the drug delivery system was able to achieve sustained and stable release of the drug.Thus,LA-CS-3TC obtained by coupling lactam-modified chitosan with lamivudine has more excellent water solubility and hepatocyte targeting compared to CS-3TC and 3TC,and has a lower cytotoxicity,is a potential application of anti-HBV drug delivery system.