title: The effect of dexamethasone/cell-penetrating peptide nanoparticles on gene delivery for inner ear therapy.
abstract: Dexamethasone (Dex)-loaded PHEA-g-C18-Arg8 (PCA) nanoparticles (PCA/Dex) were developed for the delivery of genes to determine the synergistic effect of Dex on gene expression. The cationic PCA nanoparticles were self-assembled to create cationic micelles containing an octadecylamine (C18) core with Dex and an arginine 8 (Arg8) peptide shell for electrostatic complexation with nucleic acids (connexin 26 [Cx26] siRNA, green fluorescent protein [GFP] DNA or brain-derived neurotrophic factor [BDNF] pDNA). The PCA/Dex nanoparticles conjugated with Arg8, a cell-penetrating peptide that enhances permeability through a round window membrane in the inner ear for gene delivery, exhibited high uptake efficiency in HEI-OC1 cells. This potential carrier co-delivering Dex and the gene into inner ear cells has a diameter of 120-140 nm and a zeta potential of 20-25 mV. Different types of genes were complexed with the Dex-loaded PCA nanoparticle (PCA/Dex/gene) for gene expression to induce additional anti-inflammatory effects. PCA/Dex showed mildly increased expression of GFP and lower mRNA expression of inflammatory cytokines (IL1b, IL12, and INFr) than did Dex-free PCA nanoparticles and Lipofectamine®reagent in HEI-OC1 cells. In addition, after loadingCx26siRNA onto the surface of PCA/Dex,Cx26gene expression was downregulated according to real-time polymerase chain reaction for 24 h, compared with that using Lipofectamine reagent. After loading BDNF DNA into PCA/Dex, increased expression of BDNF was observed for 30 h, and its signaling pathway resulted in an increase in phosphorylation of Akt, observed by Western blotting. Thus, Dex within PCA/Dex/gene nanoparticles created an anti-inflammatory effect and enhanced gene expression.
authors.affiliation: Department of Chemical and Biomolecular Engineering, BK 21 Plus Program, Korea Advanced Institute of Science and Technology, Guseong-Dong, Yuseong-Gu, Daejeon.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoon
authors.affiliation: Clinical Research Institute, St Mary's Hospital, Daejeon.
authors.forename: Keum-Jin
authors.initials: KJ
authors.lastname: Yang
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Shi-Nae
authors.initials: SN
authors.lastname: Park
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Dong-Kee
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Chemical and Biomolecular Engineering, BK 21 Plus Program, Korea Advanced Institute of Science and Technology, Guseong-Dong, Yuseong-Gu, Daejeon.
authors.forename: Jong-Duk
authors.initials: JD
authors.lastname: Kim
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D003907:Dexamethasone / Q000493:pharmacokinetics*; D007758:Ear, Inner / Q000166:cytology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics; D008055:Lipids; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011102:Polyhydroxyethyl Methacrylate / Q000031:analogs & derivatives / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012405:Round Window, Ear / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D057846:Cell-Penetrating Peptides; D017630:Connexins; C000607043:Gjb2 protein, mouse; D008055:Lipids; C086724:Lipofectamine; D008823:Micelles; D034741:RNA, Small Interfering; D000072259:Connexin 26; D049452:Green Fluorescent Proteins; D011102:Polyhydroxyethyl Methacrylate; C023037:poly(2-hydroxyethyl acrylate); D003907:Dexamethasone
keywords: brain-derived neurotrophic factor; cell-penetrating peptide; dexamethasone; gene delivery; nanoparticle