title: Rational modification of oligoarginine for highly efficient siRNA delivery: structure-activity relationship and mechanism of intracellular trafficking of siRNA.
abstract: Recently, cell-penetrating peptides (CPPs) have received much attention for cellular delivery of therapeutic molecules. However, in the case of CPPs as carriers for siRNA delivery, their utility is often restricted by low cellular uptake and/or entrapment in endosomes. Here, in order to deliver siRNAs with high efficiency, oligoarginine, a prominent member in CPPs, is rationally modified with oligohistidine and stearyl moieties (STR-) by fully taking into account the formation of nanoparticles, uptake and intracellular trafficking. We show that when the ratio of histidine/arginine in a peptide sequence is >1.5, pronounced gene silencing is induced. Following this rule, STR-HnR8 (n=16 and 20) are developed, which show a high knockdown efficiency rarely reported before. Finally, we find that endosomal escape of siRNA induced by stearylated and oligohistidylated oligoarginine is only from "proton-sponge" effect. Taken together, our results suggest a new strategy for the improvement of CPP-based siRNA delivery systems.
  
  
  BACKGROUND
  This study present a novel cell penetrating peptide-based siRNA delivery system utilizing modified oligo-arginine demonstrating a successful siRNA delivery approach.
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Dafeng
authors.initials: D
authors.lastname: Chu
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Ran
authors.initials: R
authors.lastname: Pan
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Weiping
authors.initials: W
authors.lastname: Sui
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada. Electronic address: p4chen@uwaterloo.ca.
authors.forename: P
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D016466:CHO Cells; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D003412:Cricetulus; D011992:Endosomes / Q000737:chemistry; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D006801:Humans; D018625:Microscopy, Atomic Force; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D057846:Cell-Penetrating Peptides; D034741:RNA, Small Interfering; D001120:Arginine
keywords: Endosomal escape; Gene silencing; Nanoparticle; Peptide; siRNA delivery