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首页> 外文期刊>Nucleic Acid Therapeutics >Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay
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Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay

机译：共轭治疗寡核苷酸的药代动力学分析：基于串血微采样的高通量法偶联肽核酸杂交测定法

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摘要

Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), hold great promise for the treatment of incurable genetically defined disorders by targeting cognate toxic gene products for degradation. To achieve meaningful tissue distribution and efficacy in vivo, siRNAs must be conjugated or formulated. Clear understanding of the pharmacokinetic (PK)/pharmacodynamic behavior of these compounds is necessary to optimize and characterize the performance of therapeutic oligonucleotides in vivo. In this study, we describe a simple and reproducible methodology for the evaluation of in vivo blood/plasma PK profiles and tissue distribution of oligonucleotides. The method is based on serial blood microsampling from the saphenous vein, coupled to peptide nucleic acid hybridization assay for quantification of guide strands. Performed with minimal number of animals, this method allowed unequivocal detection and sensitive quantification without the need for amplification, or further modification of the oligonucleotides. Using this methodology, we compared plasma clearances and tissue distribution profiles of two different hydrophobically modified siRNAs (hsiRNAs). Notably, cholesterol-hsiRNA presented slow plasma clearances and mainly accumulated in the liver, whereas, phosphocholine-docosahexaenoic acid-hsiRNA was rapidly cleared from the plasma and preferably accumulated in the kidney. These data suggest that the PK/biodistribution profiles of modified hsiRNAs are determined by the chemical nature of the conjugate. Importantly, the method described in this study constitutes a simple platform to conduct pilot assessments of the basic clearance and tissue distribution profiles, which can be broadly applied for evaluation of new chemical variants of siRNAs and micro-RNAs.
机译：诸如小干扰RNA（siRNA）的治疗性寡核苷酸对治疗可治愈的遗传定义疾病来治疗可治愈的遗传定义疾病，以靶向用于降解。为了在体内实现有意义的组织分布和功效，必须缀合或配制siRNA。清楚地了解这些化合物的药代动力学（PK）/药物动力学行为是为了优化和表征体内治疗寡核苷酸的性能。在这项研究中，我们描述了一种简单而可重复的方法，用于评估体内血液/血浆PK谱和寡核苷酸组织分布。该方法基于来自隐血静脉的连续血液微内采样，偶联至肽核酸杂交测定，用于定量导股线。用最小数量的动物进行，该方法允许明确的检测和敏感量化，而不需要扩增，或进一步修饰寡核苷酸。使用该方法，我们比较了两种不同疏水改性siRNA（Hsirnas）的等离子体间隙和组织分布谱。值得注意的是，胆固醇-HsiRNA呈现缓慢的血浆间隙并主要积聚在肝脏中，而磷光络石 - 二十二碳六烯酸-HsiRNA从血浆迅速清除，并且优选积聚在肾脏中。这些数据表明修饰的HSIRNA的PK /生物分布谱谱由缀合物的化学性质决定。重要的是，本研究中描述的方法构成了一个简单的平台，用于对基本间隙和组织分布型材进行导频评估，这可以广泛地应用于评估siRNA和微rNA的新化学变体。

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