title: Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice.
abstract: In this study, novel peptide-targeted delivery systems were developed for systemic and targeted delivery of therapeutic siRNA based on a multifunctional carrier, (1-aminoethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), which showed pH-sensitive amphiphilic cell membrane disruption. EHCO formed stable nanoparticles with siRNA. Targeted siRNA delivery systems were readily formed by surface modification of the nanoparticles. PEGylation of the siRNA/EHCO nanoparticles significantly reduced nonspecific cell uptake. The incorporation of a bombesin peptide or RGD peptide via a PEG spacer resulted in receptor-mediated cellular uptake and high gene silencing efficiency in U87 cells. Fluorescence confocal microscopic studies demonstrated that EHCO/siRNA nanoparticles and PEG modified EHCO/siRNA nanoparticles were able to facilitate endosomal escape of the siRNA delivery systems. Systemic administration of a therapeutic anti-HIF-1alpha siRNA with the peptide-targeted delivery systems resulted in significant tumor growth inhibition than a nontargeted delivery system or free siRNA via intravenous injection in nude mice bearing human glioma U87 xenografts. The results indicate a great promise of the multifunctional carrier EHCO for systemic and targeted delivery of therapeutic siRNA to treat human diseases with RNAi.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry and Neurosurgery, 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: Xueming
authors.initials: X
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Gillespie
authors.forename: Randy
authors.initials: R
authors.lastname: Jensen
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D020868:Gene Silencing / Q000502:physiology; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; D034741:RNA, Small Interfering; C047981:arginyl-glycyl-aspartic acid