Abstract

Delivery of siRNAs to blood cells is one of the most difficult tasks since there are no efficient and nontoxic methods of delivering nucleic acids to these cells in vivo. Conjugation of siRNAs with targeting or lipophilic transport molecules is one of the most promising approaches to solving this problem, since it can provide efficient accumulation without toxic side effects. Therefore, in this work, we conjugated an siRNA molecule with lipophilic molecules for its delivery to PBMC (primary blood mononuclear cells) and whole blood cells. We showed that among the studied molecules, cholesterol is the most promising agent for this purpose. Further screening of conjugates with respect to the length of the linker connecting the siRNA and cholesterol showed that a linker containing six carbon atoms is optimal for the most efficient delivery of the siRNA into human cells in experiments in whole blood. The selected siRNA–cholesterol conjugate also efficiently accumulated in mouse blood cells and splenocytes upon intravenous injection.

中文翻译：

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修饰的siRNA的亲脂性缀合物与造血细胞的体内和体外相互作用

摘要

将siRNA传递到血细胞是最困难的任务之一，因为没有有效且无毒的方法将核酸体内传递到这些细胞。siRNA与靶向或亲脂性转运分子的缀合是解决此问题的最有前途的方法之一，因为它可以提供有效的积累而不会产生毒副作用。因此，在这项工作中，我们将siRNA分子与亲脂性分子缀合在一起，以将其递送至PBMC（原代血液单核细胞）和全血细胞。我们表明，在所研究的分子中，胆固醇是用于此目的的最有希望的药物。相对于连接siRNA和胆固醇的连接子的长度进一步筛选缀合物，结果表明，在全血实验中，含六个碳原子的连接子最有效地将siRNA传递到人细胞中是最佳的。静脉注射后，选定的siRNA-胆固醇偶联物也有效地积聚在小鼠的血细胞和脾细胞中。