Dendritic molecular glues with reductively cleavable guanidinium ion pendants: Highly efficient intracellular siRNA delivery via direct translocation

Abstract

© 2018 The Chemical Society of Japan. We developed a dendritic molecular glue (GlueSS-BP) bearing multiple guanidinium ion (Gu+) pendants via a disulfide (SS) spacer as a carrier for intracellular siRNA delivery. GlueSSBP adheres tightly to siRNA and forms a stable conjugate through multivalent salt-bridge formation between the Gu+ pendants of GlueSS-BP and phosphate ions (PO41) of siRNA. The GlueSS-BP/siRNA conjugate enters living cells via direct translocation. In the cytoplasm, the SS spacers in GlueSS-BP are reductively cleaved off by glutathione (GSH) to efficiently release siRNA, thereby inducing RNA interference (RNAi). Products, formed upon reductive cleavage of GlueSS-BP in the cytoplasm, barely cause cytotoxicity.