Addition of poly (propylene glycol) to multiblock copolymer to optimize siRNA delivery

Dai, Zhi; Arévalo, Maria T; Li, Junwei; Zeng, Mingtao

RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) is an exciting, new technology with many potential biomedical applications. siRNAs are generated by cleavage of long, double-stranded RNAs (dsRNAs) by the cytoplasmic enzyme Dicer in plants and worms, 1 but can also be synthetically produced and introduced into mammalian cells to achieve gene silencing. 1, 2 Inside the cells, siRNA targets specific mRNA (mRNA) for enzymatic degradation via association with the RNA-induced silencing complex (RISC). Exploiting this system, siRNAs have been designed as promising therapies to target human diseases including those caused by viruses [3] [4] [5] [6] and cancers. [7] [8] [9] [10] [11] A major challenge of using therapeutic siRNAs in vivo is effective and safe delivery. Typically, siRNAs are 7 nm in length with an approximate molecular weight of 13 KDa 1 and have a high net negative charge. Thus, size and charge make siRNAs unable to readily penetrate cellular membranes. Furthermore, naked siR-NAs are quickly degraded by nucleases in the bloodstream, and have a short half-life of minutes in the plasma. 12 Therefore, different methods have been proposed and examined to protect and deliver siRNAs with varying degrees of success. These include use of viral vectors, cationic liposomes, and polymers.