title: A peptide-targeted delivery system with pH-sensitive amphiphilic cell membrane disruption for efficient receptor-mediated siRNA delivery.
abstract: The efficient delivery of therapeutic siRNA into cells of interest is a critical challenge to broad application of RNAi. In this study, we developed a peptide-targeted delivery system for highly efficient receptor-mediated cellular siRNA delivery. The targeted delivery system was readily prepared by in situ functionalization of a polymerizable pH-sensitive amphiphilic surfactant, N-(1-aminoethyl)iminobis[N-(oleicyl-cysteinyl-histinyl-1-aminoethyl)propionamide] (EHCO) and self-assembly with siRNA. The intrinsic pH-sensitive amphiphilicity of EHCO at pH 5-6 was able to induce cell membrane disruption at endosomal pH and facilitate endosomal escape of the siRNA nanoparticles after internalization. The siRNA/EHCO nanoparticles and PEGylated siRNA/EHCO nanoparticles were not cytotoxic as compared to PEI/siRNA or TransFast/siRNA nanoparticles. siRNA/EHCO nanoparticles resulted in higher siRNA delivery efficiency than PEI and TransFast. The PEGylation of the siRNA/EHCO nanoparticles significantly reduced non-specific cell uptake. The incorporation of a bombesin peptide via a PEG spacer resulted in specific cellular uptake and high gene silencing efficiency in CHO-d1EGFP cells with overexpression of bombesin receptors. Receptor-mediated endocytosis and pH-sensitive amphiphilic endosomal escape are the advantageous features of the targeted siRNA delivery system for highly efficient cell-specific siRNA delivery. This novel targeted delivery system holds a great promise for systemic and targeted delivery of therapeutic siRNA.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84108, USA.
authors.forename: Xu-Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Rongzuo
authors.initials: R
authors.lastname: Xu
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D011992:Endosomes / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D004337:Drug Carriers; D008024:Ligands; C541916:N-(1-aminoethyl)iminobis(N-(oleoyl-cysteinyl-histidyl-1-aminoethyl)propionamide); D010446:Peptide Fragments; D034741:RNA, Small Interfering; D018004:Receptors, Bombesin; D013501:Surface-Active Agents; C118536:bombesin (7-14); D001839:Bombesin