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 (logP) 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 0.032mg/ml. The micelles with 1mg/ml CSO-SA concentration had 460.8nm average diameters with a narrow size distribution and 29.7mV 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.
Li
Qian
Q
College of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Du
Yong-Zhong
YZ
Yuan
Hong
H
Zhang
Xing-Guo
XG
Miao
Jing
J
Cui
Fu-De
FD
Hu
Fu-Qiang
FQ
D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry*; D016503:Drug Delivery Systems; D006515:Hepatitis B virus / Q000187:drug effects; D019259:Lamivudine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008823:Micelles; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry*
D000998:Antiviral Agents; D008823:Micelles; D009844:Oligosaccharides; D013229:Stearic Acids; D019259:Lamivudine; D048271:Chitosan