Albumin-Binding Aptamer Chimeras for Improved siRNA Bioavailability.
Albumin-Binding Aptamer Chimeras for Improved siRNA Bioavailability.
复制标题
白蛋白结合适体嵌合体可提高 siRNA 生物利用度。
DOI：
10.1007/s12195-022-00718-y
复制
发表时间：
2022
影响因子：
2.8
通讯作者：
Lippmann,EthanS
中科院分区：
文献类型：
--
作者：
Rosch,JonahC;Hoogenboezem,EllaN;Sorets,AlexanderG;Duvall,CraigL;Lippmann,EthanS
短干扰rna （sirna）是有效的基于核酸的药物，设计用于靶向疾病驱动基因，否则可能无法用小分子药物治疗。然而，sirna在体内的治疗潜力受到较差的药代动力学特性的限制，包括快速的肾脏清除和核酸酶降解。利用血清中浓度高、半衰期长的白蛋白等天然载体，是改变生物利用度差的生物药物的药代动力学的有效途径。在这项工作中，我们试图开发白蛋白结合适体-siRNA嵌合体，以提高siRNA的生物利用度。方法采用指数富集法（SELEX）系统进化配体（Systematic Evolution of Ligands through Exponential Enrichment， SELEX）获得修饰的rna结合适体，然后通过体外转录直接与siRNA融合。随后在体外和体内测量了适体- sirna嵌合体的分子和药代动力学特性。结果体外检测显示，在嵌合体形态下，白蛋白结合适体在血清中稳定存在，同时保持了强大的基因敲除能力。在体内，表现最好的适体- sirna嵌合体（克隆1）的绝对循环半衰期比混乱的适体嵌合体对照组高1.6倍。结论saptamer - sirna嵌合体在不影响生物活性的前提下提高了生物利用度。因此，这种结合白蛋白的适体- sirna嵌合体方法可能是一种很有前途的药物递送应用策略。
IntroductionShort interfering RNAs (siRNAs) are potent nucleic acid-based drugs designed to target disease driving genes that may otherwise be undruggable with small molecules. However, therapeutic potential of siRNAin vivois limited by poor pharmacokinetic properties, including rapid renal clearance and nuclease degradation. Backpacking on natural carriers such as albumin, which is present at high concentration and has a long half-life in serum, is an effective way to modify pharmacokinetics of biologic drugs that otherwise have poor bioavailability. In this work, we sought to develop albumin-binding aptamer-siRNA chimeras to improve the bioavailability of siRNA.MethodsA Systematic Evolution of Ligands through Exponential Enrichment (SELEX) approach was used to obtain modified RNA-binding aptamers, which were then fused directly to siRNA viain vitrotranscription. Molecular and pharmacokinetic properties of the aptamer-siRNA chimeras were subsequently measuredin vitroandin vivo.ResultsIn vitroassays show that albumin-binding aptamers are stable in serum while maintaining potent gene knockdown capabilities in the chimera format.In vivo, the absolute circulation half-life of the best-performing aptamer-siRNA chimera (Clone 1) was 1.6-fold higher than a scrambled aptamer chimera control.ConclusionsAptamer-siRNA chimeras exhibit improved bioavailability without compromising biological activity. Hence, this albumin-binding aptamer-siRNA chimera approach may be a promising strategy for drug delivery applications.