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靶向给药能够增加局部药物的浓度,提高疗效,减少不良反应。目前实现药物靶向性的重要策略是使用靶向载体,如抗体、肽、天然或人工合成的聚合物、糖或肽标记的毫微粒和脂质体等。但这些方法有很多不足,如难以通过内皮细胞到达血管外靶点、生产成本高、共轭物诱导免疫原反应、载药量有限及给药方式不便等。Erion等人发现了一类新的磷酸酯和膦酸酯前药,取名为HepDirect前药。该类前药可以特异性地被肝细胞CYP450同工酶CYP3A4酶氧化,释放活性形式的核苷酸或核苷膦酸。经动物和人体试验,HepDirect前药具有明显的肝靶向性,未发现与副产物相关的毒性。文中通过查阅近几年的相关文献,对核苷类HepDirect前药的原理、稳定性、副产物、代表药物等进行综述。
Targeted drug delivery can increase the concentration of local drugs, improve efficacy, reduce adverse reactions. Currently, an important strategy for drug targeting is to use targeting vectors such as antibodies, peptides, natural or synthetic polymers, sugar or peptide labeled nanoparticles and liposomes and the like. However, these methods have many shortcomings, such as difficult access to extravascular targets by endothelial cells, high production costs, conjugate-induced immunogenic reactions, limited drug loading, and inconvenient administration. Erion et al. Have discovered a new class of phosphate and phosphonate prodrugs, which are known as HepDirect prodrugs. Such prodrugs can be specifically oxidized by the hepatocyte CYP450 isoenzyme CYP3A4 enzyme to release the active form of nucleotides or nucleoside phosphonates. In animal and human trials, HepDirect prodrugs showed significant liver targeting and no by-product toxicities were found. Through reviewing the related literatures in recent years, the principle, stability, by-products and representative drugs of nucleoside HepDirect prodrugs are reviewed.