Interplay of polyethyleneimine molecular weight and oligonucleotide backbone chemistry in the dynamics of antisense activity.
Interplay of polyethyleneimine molecular weight and oligonucleotide backbone chemistry in the dynamics of antisense activity.
复制标题
反义活性动力学中聚乙烯亚胺的分子量和寡核苷酸骨架化学的相互作用。
DOI：
10.1093/nar/gkm450
复制
发表时间：
2007
影响因子：
14.9
通讯作者：
Roth, Charles M
中科院分区：
文献类型：
--
作者：
Sundaram, Sumati;Lee, Li Kim;Roth, Charles M
基因沉默技术的广泛应用，如反义，受到寡核苷酸（ON）的不良细胞递送的阻碍。用于增强ON递送的载体的合理设计需要更好地理解载体对反义效应的程度和时间过程的作用。本研究的目的是了解聚合物分子量（MW）和ON骨架化学对反义活性的影响。在不同分子量的支化聚乙烯亚胺（PEI）与磷酸二酯和硫代磷酸酯化学物质的ON之间制备复合物。我们测量了它们的物理化学性质，并评估了它们向细胞递送ON的能力，从而导致反义反应。我们的关键发现是，反义活性不仅由PEI MW或ON化学决定，而是由两种因素的相互作用决定。虽然靶mRNA下调的程度主要由聚合物MW决定，但动力学主要由ON化学决定。特别重要的是载体和ON之间的相互作用强度，它决定了ON在细胞内递送的速率。我们还提出了一个数学模型的反义过程中强调的重要性，对反义下调。
The widespread utilization of gene silencing techniques, such as antisense, is impeded by the poor cellular delivery of oligonucleotides (ONs). Rational design of carriers for enhanced ON delivery demands a better understanding of the role of the vector on the extent and time course of antisense effects. The aim of this study is to understand the effects of polymer molecular weight (MW) and ON backbone chemistry on antisense activity. Complexes were prepared between branched polyethyleneimine (PEI) of various MWs and ONs of phosphodiester and phosphorothioate chemistries. We measured their physico-chemical properties and evaluated their ability to deliver ONs to cells, leading to an antisense response. Our key finding is that the antisense activity is not determined solely by PEI MW or by ON chemistry, but rather by the interplay of both factors. While the extent of target mRNA down-regulation was determined primarily by the polymer MW, dynamics were determined principally by the ON chemistry. Of particular importance is the strength of interactions between the carrier and the ON, which determines the rate at which the ONs are delivered intracellularly. We also present a mathematical model of the antisense process to highlight the importance of ON delivery to antisense down-regulation.