脂质体的乳糖化修饰及其肝脏靶向性研究

Study of lactosaminated liposome and its hepatotropic targeting in rats

目的探讨乳糖化白蛋白－脂质体交联物（简称交联物）作为肝脏靶向性药物载体的可行性。方法应用生物化学技 术合成交联物并对大鼠进行体内实验，了解交联物在动物肝脏的聚集量以及预先注射乳糖化白蛋白对交联物肝脏聚集 性的抑制作用；比较交联物、普通脂质体分别包裹的 α－干扰素及游离 α－干扰素在 ２．２．１５细胞中的抗乙型肝炎病毒效 应。结果交联物在肝脏的聚集量是脾脏的２倍以上，是其他脏器的４－９倍；预先注射乳糖化白蛋白后交联物的肝脏聚 集性减弱，与脾脏聚集量无显著差异；交联物包裹干扰素后抗乙肝病毒效应较普通脂质体包裹的干扰素及游离干扰素 显著提高，相当于普通脂质体干扰素１／４剂量、游离干扰素１／８剂量的抗病毒效应。结论文联物通过去唾液酸糖蛋白受 体实现肝脏聚集性，可望成为理想的肝脏靶向性药物载体。

Objective To study the feasibility of conjugating lactosaminated human serum albumin and liposomes as a carrier for drugs targeted at the liver. Methods Lactosaminated human serum albumin was covalently coupled with liposomes, using biofunctional reagent N- succinimidyl- S-acetylthioacetate. Labeled with 131I, the conjugate was injected into rat tail vein to ob- serve its accumulation in the liver and the inhibitory effect of pre-injected lactosaminated albumin on the accumulation. The inhibitory effects of the conjugate- and liposome-encapsulated interferon-a on hepatitis B virus (HBV) replication were observed and compared in 2.2. 15 cells treated with the 2 preparations. Results The accumulation of the conjugate in the rat liver was twice as much as in the spleen (P<0.01), and 4 to 9 times as in other organs (P<0.01). Pre-injection of lactosaminated albumin did not affect the accumulation of the conjugate in the liver and spleen (P>0.05). When encapsulated by the conjugate, interferon-a showed enhanced inhibitory effect on HBV replication compared with that of liposome-encapsulated interferon-a (0.01<P<0.05) and free interferon-a (P<0.05), and to achieve similar inhibitory effect, the dosage of conjugate- encapsulated interferon-a was only l/4 and l/8 of that required by the latter 2 respectively. Conclusion The conjugate of lactosaminated albumin and liposomes is targeted at the liver guided by asialoglycoprotein receptor, and has the potential for application as a carrier for drugs targeted at the liver.