Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, MA 02142, USA.
J Control Release. 2010 Jun 1;144(2):227-32. doi: 10.1016/j.jconrel.2010.02.011. Epub 2010 Feb 17.
Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2'-3'-cyclic nucleotide 3'-phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo.
将小干扰 RNA（siRNA）与亲脂性分子缀合已被证明可以增强细胞摄取，并且在全身给药后在肝脏中产生有效的内源性基因沉默，在直接局部注射后在神经元中产生有效的内源性基因沉默。在这里，我们通过针对少突胶质细胞中的 CNPase（2'-3'-环核苷酸 3'-磷酸二酯酶）来评估与胆固醇缀合的不同连接子的 siRNA 的体内递送。通过脑室内中枢神经系统（CNS）输注向大鼠胼胝体给药的胆固醇缀合的 siRNA 与未缀合的 siRNA 相比显示出改善的沉默能力。此外，用可裂解的二硫键连接子将 siRNA 缀合到胆固醇上似乎有利于提高体内少突胶质细胞中 CNPase mRNA 沉默的效力。总之，这些发现表明胆固醇缀合的 siRNA 可有效直接递送至少突胶质细胞的中枢神经系统，并且生物可裂解的二硫键连接子似乎有利于提高体内靶 mRNA 沉默的效力。
