Receptor-mediated delivery of drugs to hepatocytes
Receptor-mediated delivery of drugs to hepatocytes
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DOI：
10.1016/0169-409x(89)90037-9
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发表时间：
1989-07
影响因子：
16.1
通讯作者：
R. Fallon;A. Schwartz
中科院分区：
文献类型：
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作者：
R. Fallon;A. Schwartz
治疗肝脏疾病的标准药理学方法由于活性剂向肝细胞中的递送不足以及对其他器官的非特异性毒性而受挫。通过药物-配体或大分子-配体复合物与细胞表面受体结合，随后在细胞内内胞吞和释放，药物靶向肝细胞可以提高药物的治疗率。存在几种对肝实质细胞特异的受体分子，并且可以提供这样的药物递送功能。一种这样的受体，脱唾液酸糖蛋白（ASGP）受体已经在肝细胞以及分化良好的肝癌细胞系HepG 2中进行了研究。该细胞系在许多代谢、合成和结构特征方面类似于成熟肝细胞。在该模型系统中，与受体结合的配体通过包被的小坑内化并进入酸性隔室，在那里发生配体-受体解离，随后受体再循环至质膜，并最终将配体转移至溶酶体进行降解。在肝细胞和HepG 2细胞系中也阐明了其他不会导致配体降解的细胞内途径。这已经在ASGP受体、转铁蛋白受体和多聚Ig-IgA受体中得到证实。显然，与这些受体中的任一种的配体复合的大分子药理学试剂（例如单克隆抗体、酶或核酸）必须从配体解离并渗透内体膜以到达其细胞内作用位点。最近的研究病毒的发病机制和细胞内的蛋白质靶向揭示了关键功能的蛋白质结构域的结构是必要的膜渗透。对这些细胞内分选途径的机制的进一步理解将使药物载体设计能够充分利用肝细胞受体介导的内吞作用用于药物递送的潜力。
Standard pharmacologic approaches to liver diseases have been frustrated by inadequate delivery of active agents into liver cells as well as nonspecific toxicity towards other organs. Drug targeting to hepatocytes via the binding of a drug-ligand or macromolecule-ligand complex to a cell surface receptor with subsequent endocytosis and release within the cell may improve the drug's therapeutic ratio. Several receptor molecules specific for liver parenchymal cells exist and could serve such a drug-delivery function. One such receptor, the asialoglycoprotein (ASGP)-receptor has been studied in hepatocytes as well as in a well-differentiated hepatoma cell line, HepG2. This cell line resembles mature hepatocytes in many metabolic, synthetic, and structural features. In this model system, ligand bound to receptor is internalized via coated pits and enters an acidic compartment where ligand-receptor dissociation occurs followed by receptor recycling to plasma membrane and eventual transfer of ligand to lysosome for degradation. Other intracellular routes not resulting in degradation of ligand have also been elucidated in hepatocytes and the HepG2 cell line. This has been demonstrated for the ASGP receptor, the transferrin receptor and the polymeric Ig-IgA receptor. It is apparent that macromolecular pharmacologic agents complexed to ligands for any of these receptors (such as monoclonal antibodies, enzymes, or nucleic acids) must dissociate from the ligand and permeate the endosomal membrane to reach their intracellular sites of action. Recent studies of viral pathogenesis and intracellular protein targeting have revealed key features of protein domain structure that are necessary for membrane permeation. Further understanding of the mechanisms responsible for these pathways of intracellular sorting will enable drug-carrier design that will fully exploit the potential of hepatocyte receptor-mediated endocytosis for drug delivery.