Fiume L, Di Stefano G, Busi C, Mattioli A, Bonino F, Torrani-Cerenzia M, Verme G, Rapicetta M, Bertini M, Gervasi G B
Dipartimento di Patologia Sperimentale, Università di Bologna, Italy.
J Viral Hepat. 1997;4(6):363-70. doi: 10.1046/j.1365-2893.1997.00067.x.
In order to reduce the extrahepatic side-effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara-AMP), conjugated with lactosaminated human serum albumin (L-HSA) and administered to hepatitis B virus (HBV)-infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side-effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine (Lac-poly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac-poly(Lys) conjugates, one with ara-AMP and one with ribavirin, are reported in this review.
为了减少抗病毒核苷类似物在治疗慢性病毒性肝炎时的肝外副作用，这些药物与半乳糖基末端大分子结合。结合物中的载体半乳糖残基与仅在这些细胞上大量且高亲和力存在的去唾液酸糖蛋白受体相互作用后，选择性地进入肝细胞。在肝细胞内，结合物被输送到溶酶体，在那里酶将载体与药物之间的键切断，使药物能够在肝脏中浓缩。一项临床研究证实了这种化疗策略的有效性。单磷酸阿糖腺苷（ara-AMP）与乳糖胺化人血清白蛋白（L-HSA）结合，并给予乙型肝炎病毒（HBV）感染患者28天，其抗病毒活性与游离药物相同，且未产生任何临床副作用，包括游离药物引起的严重神经毒性。目前正在进行临床前研究，使用乳糖胺化聚-L-赖氨酸（Lac-poly(Lys)）作为亲肝载体获得结合物。这些新的结合物比用L-HSA制备的结合物具有一些优势：它们可以通过肌肉注射途径给药；它们完全通过化学合成获得，从而消除了使用血液衍生物所涉及的问题；它们的药物负载量高，这允许给予更少量的结合物，这些结合物在溶酶体中更容易被消化；并且它们能够将更多量的药物引入肝细胞。本文综述了两种Lac-poly(Lys)结合物的实验结果，一种与ara-AMP结合，另一种与利巴韦林结合。
