College of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Eur J Pharm Sci. 2010 Nov 20;41(3-4):498-507. doi: 10.1016/j.ejps.2010.08.004. Epub 2010 Aug 20.
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.
为了提高水溶性抗病毒药物拉米夫定（LA）的亲脂性，通过 LA 与硬脂酸之间的酯键合成了 LA 的前药硬脂酸拉米夫定（LAS）。酯化后，LA 的辛醇-水分配系数（logP）从-0.95 增加到 1.82。硬脂酸-g-壳聚糖寡糖（CSO-SA）胶束已证明具有快速内化和积聚肿瘤细胞的能力。在此，制备了取代度（SD）为 3.79%的 CSO-SA 负载 LAS。CSO-SA 的临界胶束浓度（CMC）约为 0.032mg/ml。CSO-SA 浓度为 1mg/ml 的胶束具有 460.8nm 的平均粒径，具有较窄的粒径分布和 29.7mV 的表面 Zeta 电位。掺入 LAS 后，胶束粒径减小，Zeta 电位增加。载有 LAS 的 CSO-SA 胶束（CSO-SA/LAS）具有较高的包封效率和载药量。CSO-SA/LAS 中的 LA 释放呈现 pH 依赖性。当释放介质的 pH 从 7.4 降低至 6.2 时，LA 从 CSO-SA/LAS 的释放速率显著增加。CSO-SA/LAS 表现出低细胞毒性和高转染 HBV 的肿瘤细胞（HepG2.2.15）对 LAS 的摄取百分比。与 LA 和 LAS 相比，CSO-SA/LAS 的体外抗 HBV 活性对抗原表达和 DNA 复制具有更明显的抑制作用。
