Current status of delivery systems to improve target efficacy of oligonucleotides.
Current status of delivery systems to improve target efficacy of oligonucleotides.
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DOI：
10.2174/1381612043453009
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发表时间：
2004-02
影响因子：
3.1
通讯作者：
Y. Shoji;H. Nakashima
中科院分区：
文献类型：
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作者：
Y. Shoji;H. Nakashima
基因治疗的悲剧性失败导致了基因医学研究的倒退。由于基于基因的药物，如反义寡核苷酸、核酶、三链体或基因在体外和体内的传递较差，基于基因的药物作为治疗剂的进一步开发已经停滞。尽管递送系统对寡核苷酸的整体疗效起着关键作用，但靶点选择不当、评价方法不当以及对结果的误解往往导致悲观的看法。尽管如此，整个人类基因组的解码重新点燃了基因医学传递工具的热情。本文主要介绍近年来发展起来的以反义寡核苷酸为载体的药物输送系统。提高反义寡核苷酸递送效率的方法有两种：一种是对反义寡核苷酸骨架进行化学修饰。另一种方式是通过递送载体，如阳离子脂质体、合成聚合物或非病毒载体。我们将回顾目前的状况，在体外和体内的运载工具。递送效率取决于寡核苷酸的化学性质、长度、大小、净电荷、细胞/组织类型和施用途径。很难推断出影响交付效率的共同规则。一些细胞如角质形成细胞在没有递送系统的情况下快速内化寡核苷酸，这与通常的看法相反。虽然我们不能广泛地涵盖所有的报告，我们将总结几个实验与交付系统在体外和体内。然后，我们将讨论促进寡核苷酸有效递送的可能因素。
The tragic failure of gene therapy resulted in rolling back the research of gene-based medicine. Because of the poor delivery of gene-based medicines, such as antisense oligonucleotides, ribozyme, triplex, or gene both in vitro and in vivo, further development of gene-based medicines as therapeutic agents have stagnated. Although the delivery system plays a critical role in the overall efficacy of oligonucleotides, inappropriate target selection, improper evaluation methods and misinterpretation of results often caused the pessimistic view. Still, the decoding of the whole human genome has rekindled the enthusiastic development of delivery tools for gene-based medicine. We would like to focus on the newly developed delivery systems mainly for antisense oligonucleotides in this article. There are two ways to improve delivery efficacy of antisense oligonucleotides: One is the chemical modification of the antisense oligonucleotide backbone. The other way is by means of delivery vehicles, such as cationic liposomes, synthetic polymers, or non-viral vectors. We will review the current status of delivery vehicles both in vitro and in vivo. Delivery efficiency depends on the oligonucleotides' chemistry, length, size, net charge, cell/tissue type and administration route. It is difficult to deduce a common rule that affects delivery efficiency. Some cells like keratinocytes rapidly internalize oligonucleotides without a delivery system, which is contrary to common belief. Although we cannot extensively cover all reports, we will summarize several experiments with delivery system in vitro and in vivo. We will then address the possible factors promoting the efficient delivery of oligonucleotides.