Synthesis of Lamivudine stearate and antiviral activity of stearic acid-g-chitosan oligosaccharide polymeric micelles delivery system

To increase lipophilicity of water-soluble antiviral drug, the prodrug of Lamivudine (LA), Lamivudine stearate (LAS) was synthesized via ester linkage between LA and stearic acid. After the esterification, the octanol–water partition coefficient (log P) of LA increased from −0.95 to 1.82. Stearic acid-g-chitosan oligosaccharide (CSO-SA) micelles have demonstrated fast internalization and accumulation ability to tumor cells. Herein, the CSO-SA with 3.79% amino substitution degree (SD) was prepared for loading LAS. The critical micelle concentration (CMC) of CSO-SA was about 0.032 mg/ml. The micelles with 1 mg/ml CSO-SA concentration had 460.8 nm average diameters with a narrow size distribution and 29.7 mV surface zeta potential. After LAS was incorporated, the micellar size decreased and the zeta potential increased. The LAS loaded CSO-SA micelles (CSO-SA/LAS) possessed high entrapment efficiency and drug loading. LA release from CSO-SA/LAS showed a pH-dependent behavior. The release rate of LA from CSO-SA/LAS increased significantly as the pH of release medium reduced from 7.4 to 6.2. CSO-SA/LAS presented a low cytotoxicity and high cellular uptake percentage of LAS against HBV transfected tumor cells (HepG2.2.15). In vitro anti-HBV activities of CSO-SA/LAS presented more conspicuous inhibitory effects on antigen expression and DNA replication compared with LA and LAS.