Albumin-Binding Fatty Acid-Modified Gapmer Antisense Oligonucleotides for Modulation of Pharmacokinetics
Albumin-Binding Fatty Acid-Modified Gapmer Antisense Oligonucleotides for Modulation of Pharmacokinetics
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DOI：
10.1007/978-1-0716-0771-8_12
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Howard, Kenneth A.
中科院分区：
文献类型：
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作者：
Cai, Yunpeng;Lou, Chenguang;Howard, Kenneth A.
延长循环和药代动力学特征的调节对于提高反义寡核苷酸（ASO）的临床潜力非常重要。 Gapmer ASO 表现出优异的核酸酶稳定性和强大的基因沉默活性，无需转染剂。然而，体内应用的一个主要挑战是血液循环半衰期短。这项工作描述了利用血清白蛋白的长循环来增加gapmer ASO 的血液停留时间。该方法将脂肪酸修饰引入间隙聚体 ASO 设计中，以利用血清白蛋白与内源配体的结合和运输特性。白蛋白-缺口聚体 ASO 相互作用的水平、血液循环半衰期和生物分布取决于缺口聚体 ASO 序列内的数量、位置和脂肪酸类型（棕榈酸或肉豆蔻酸）以及硫代磷酸酯或磷酸二酯主链修饰。这项工作提供了一种通过提出的血清白蛋白内源组装过程来优化gapmer ASO药代动力学的策略，该过程可以通过gapmer ASO设计修改进行调整。
Prolonged circulation and modulation of the pharmacokinetic profile are important to improve the clinical potential of antisense oligonucleotides (ASOs). Gapmer ASOs demonstrate excellent nuclease stability and robust gene silencing activity without the requirement of transfection agents. A major challenge for in vivo applications, however, is the short blood circulatory half-life. This work describes utilization of the long circulation of serum albumin to increase the blood residence time of gapmer ASOs. The method introduces fatty acid modifications into the gapmer ASOs design to exploit the binding and transport property of serum albumin for endogenous ligands. The level of albumin-gapmer ASOs interaction, blood circulatory half-life and biodistribution was dependent on number, position, and fatty acid type (palmitic or myristic acid) within the gapmer ASO sequence and either phosphorothioate or phosphodiester backbone modifications. This work offers a strategy to optimize gapmer ASO pharmacokinetics by a proposed endogenous assembly process with serum albumin that can be tuned by gapmer ASO design modifications.