Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Adv. 2019 Feb 20;5(2):eaav9322. doi: 10.1126/sciadv.aav9322. eCollection 2019 Feb.
Nonhepatic delivery of small interfering RNAs (siRNAs) remains a challenge for development of RNA interference-based therapeutics. We report a noncationic vector wherein linear poly(ethylene glycol) (PEG), a polymer generally considered as inert and safe biologically but ineffective as a vector, is transformed into a bottlebrush architecture. This topology provides covalently embedded siRNA with augmented nuclease stability and cellular uptake. Consisting almost entirely of PEG and siRNA, the conjugates exhibit a ~25-fold increase in blood elimination half-life and a ~19-fold increase in the area under the curve compared with unmodified siRNA. The improved pharmacokinetics results in greater tumor uptake and diminished liver capture. Despite the structural simplicity these conjugates efficiently knock down target genes in vivo without apparent toxic and immunogenic reactions. Given the benign biological nature of PEG and its widespread precedence in biopharmaceuticals, we anticipate the brush polymer-based technology to have a significant impact on siRNA therapeutics.
非肝脏递送小干扰 RNA（siRNA）仍然是 RNA 干扰治疗发展的一个挑战。我们报告了一种非阳离子载体，其中线性聚乙二醇（PEG），一种通常被认为是惰性和安全的生物聚合物，但作为载体无效，被转化为刷型聚合物结构。这种拓扑结构为共价嵌入的 siRNA 提供了增强的核酸酶稳定性和细胞摄取。该缀合物几乎完全由 PEG 和 siRNA 组成，与未修饰的 siRNA 相比，其血液消除半衰期增加了约 25 倍，曲线下面积增加了约 19 倍。改善的药代动力学导致更多的肿瘤摄取和减少的肝脏捕获。尽管结构简单，但这些缀合物在体内有效地敲低了靶基因，没有明显的毒性和免疫原性反应。考虑到 PEG 的良性生物学性质及其在生物制药中的广泛先例，我们预计基于刷状聚合物的技术将对 siRNA 治疗产生重大影响。
