肝靶向抗病毒药NGA-ACV的制备及其趋肝性

以无唾液酸糖蛋白受体(asialoglycoprotein receptor,ASGP-R)的特异性配体——半乳糖基拟糖白蛋白(neoglycoalbumin,NGA)为载体,通过丁二酰基桥将抗病毒药无环鸟苷(acyclovir,ACV)与NGA偶联,得到肝靶向抗病毒药NGA-ACV。差热分析和高效液相色谱分析结果表明,NGA-ACV是共价键偶联物,且在血液中稳定性很好。将偶联物用¹³¹I标记后进行家兔放射性显像比较研究。结果,高、低药密度NGA-ACV的肝脏放射性分别是全身放射性的81.6%和86.6%,其趋肝性无明显差别。研究小鼠体内高药密度¹³¹I-NGA-ACV的分布,在5min时肝脏放射性达到峰值,为注入量的81.7±10.4%。受体竞争抑制实验表明NGA-ACV的肝靶向机理为受体介导的主动靶向过程。初步体外抗乙肝病毒比较研究表明,NGA-ACV较ACV的抗病毒剂量有明显降低。

PREPARATION OF HEPATIC TARGETING ANTIVIRUS AGENT NGA-ACV AND ITS TARGETING PROPERTY

Neoglycoalbumin (NGA), a special ligend of asialoglycoprotein receptor on the hepatocyte, was linked via a butanediacyl bridge to acyclovir to form a conjugate NGA-ACV. By using DTA (Differential thermoanalysis ) and HPLC analysis, ACV was shown to be connected with NGA by covalent bonds and stable in blood. The radio biodistribution of ¹³¹I-NGA-ACV with high drug density in vivo was carried out in mice. The maximum absorption of ¹³¹I-NGA-ACV in liver was 81.7±10.4% at 5 min. The radio image of ¹³¹I-NGA-ACV with high or low drug density in rabbit showed no significant difference in liver targeting property. The competitive connection tests indicated that ¹³¹I-NGA-ACV was concentrated in liver through receptor mediated mechanism. A tentative test of antihepatitis B of NGA ACV and ACV in vitro showed that the effective dose of the former was significantly lower than that of the latter.