PDF(Pubmed)
Abstract：
Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge. Conjugating lipids (e.g., docosanoic acid [DCA]) to siRNA supports extrahepatic delivery, but tissue accumulation remains lower than that achieved in liver by approved siRNA therapeutics. Early evidence suggests that functionalizing DCA with a head group (e.g., phosphatidylcholine [PC]) may enhance delivery to certain tissues. Here, we report the first systematic evaluation of the effect of PC head group chemistry on the extrahepatic distribution of DCA-conjugated siRNAs. We show that functionalizing DCA with a PC head group enhances siRNA accumulation in heart, muscle, lung, pancreas, duodenum, urinary bladder, and fat. Varying the size of the linker between the phosphate and choline moiety of the PC head group altered the extrahepatic accumulation of siRNA, with the optimal linker length being different for different tissues. Increasing PC head group valency also improved extrahepatic accumulation in a tissue-specific manner. This study demonstrates the structural impact of the PC moiety on the biodistribution of lipid-conjugated siRNA and introduces multiple novel PC variants for the chemical optimization of DCA-conjugated siRNA. These chemical variants can be used in the context of other lipids to increase the repertoire of conjugates for the extrahepatic distribution of siRNAs.
摘要：
小干扰RNA（siRNA）正在彻底改变肝脏相关适应症的治疗。然而，强大的传递到肝外组织仍然是一个挑战。缀合脂质(例如，二十二烷酸[DCA]）对siRNA支持肝外递送，但是组织积累仍然低于批准的siRNA疗法在肝脏中实现的积累。早期证据表明，用头组将DCA功能化(例如，磷脂酰胆碱[PC]）可以增强对某些组织的递送。这里,我们报告了首次系统评估PC头组化学对DCA缀合的siRNA肝外分布的影响。我们表明，用PC头部基团功能化DCA可增强siRNA在心脏中的积累，肌肉，肺，胰腺,十二指肠,膀胱,和脂肪。改变PC头部基团的磷酸盐和胆碱部分之间的接头的大小改变了siRNA的肝外积累,最佳接头长度对于不同的组织是不同的。PC头组效价的增加也以组织特异性方式改善了肝外积累。这项研究证明了PC部分对脂质缀合的siRNA的生物分布的结构影响，并引入了多种新型PC变体用于DCA缀合的siRNA的化学优化。这些化学变体可用于其他脂质的背景中,以增加用于siRNA的肝外分布的缀合物的库。
