title: Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.
abstract: Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Jingga
authors.initials: J
authors.lastname: Morry
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Worapol
authors.initials: W
authors.lastname: Ngamcherdtrakul
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Shenda
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Goodyear
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA; PDX Pharmaceuticals, LLC, 24 Independence Ave, Lake Oswego, OR 97035, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Castro
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Reda
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
authors.forename: Thanapon
authors.initials: T
authors.lastname: Sangvanich
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA; PDX Pharmaceuticals, LLC, 24 Independence Ave, Lake Oswego, OR 97035, USA. Electronic address: yantasee@ohsu.edu.
authors.forename: Wassana
authors.initials: W
authors.lastname: Yantasee
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics*; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D058608:Nanopores / Q000648:ultrastructure; D010316:Particle Size; D016062:Porosity; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D045743:Scleroderma, Diffuse / Q000235:genetics* / Q000628:therapy*; D012822:Silicon Dioxide / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D050958:HSP47 Heat-Shock Proteins; D053769:Nanocapsules; D034741:RNA, Small Interfering; C494661:Serpinh1 protein, mouse; D012822:Silicon Dioxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: Dermal delivery; Fibrosis; HSP47; MSNP; NOX4; siRNA