Dendritic Molecular Glues with Reductively Cleavable Guanidinium Ion Pendants: Highly Efficient Intracellular siRNA Delivery via Direct Translocation

摘要

We developed a dendritic molecular glue (Glue(SS)-BP) bearing multiple guanidinium ion (Gu(+)) pendants via a disulfide (SS) spacer as a carrier for intracellular siRNA delivery. Glue(SS)-BP adheres tightly to siRNA and forms a stable conjugate through multivalent salt-bridge formation between the Gu(+) pendants of Glue(SS)-BP and phosphate ions (PO4-) of siRNA. The Glue(SS)-BP/siRNA conjugate enters living cells via direct translocation. In the cytoplasm, the SS spacers in Glue(SS)-BP are reductively cleaved off by glutathione (GSH) to efficiently release siRNA, thereby inducing RNA interference (RNAi). Products, formed upon reductive cleavage of Glue(SS)-BP in the cytoplasm, barely cause cytotoxicity.