已上市核酸类药物的制剂学研究进展

Progress in the Formulation of Approved Nucleic Acid Drugs

近年来,随着对疾病基因相关机制的不断深入研究,包括质粒DNA、反义寡核苷酸、小干扰RNA、微小RNA及其他基因疗法在内的核酸类药物,引发了全球的广泛关注,其中一些核酸类药物已获得批准上市,用于临床治疗。然而,核酸在体液和细胞内运输所面临的一系列障碍,如容易在血液中快速降解、肝肾清除速度快、细胞摄取效率低以及难以从内吞体逃逸等问题,极大阻碍了核酸类药物的临床应用。病毒和非病毒基因传递系统能将基因传递至胞浆或细胞核,并显示出良好的疗效,已成为核酸类药物体内递送的主要技术手段。本文主要介绍核酸类药物在机体内传递的各种挑战,总结近年来已获批上市的核酸类药物的发展,同时重点从制剂学角度探讨这些已上市的核酸类药物所采用的基因传递系统特点。

In recent years,due to the enhanced knowledge about the genetic basis of disease,nucleic acid drugs including plasmid DNA,antisense oligonucleotide,small interfering RNA,microRNA,and other gene-based therapies have drawn wide attention on a global scale,and some of these nucleic acid drugs have been approved for clinical use.However,a series of systemic and intracellular obstacles for gene delivery,such as fast degradation in blood,rapid hepatic and renal clearance,low cellular uptake efficiency,and inefficient endosomal escape,have greatly hindered the development of nucleic acid drugs.Therefore,viral and non-viral gene delivery systems become the major technological means to transport genes to reach cytosol or cell nucleus,and to achieve therapeutic effect.In this review,we introduce the barriers and challenges of gene delivery in vivo,summarize recent advances on the approved nucleic acid drugs,and mainly discuss their delivery systems from the aspects of formulations.