title: Hyaluronan nanoparticles bearing γ-secretase inhibitor: in vivo therapeutic effects on rheumatoid arthritis.
abstract: γ-Secretase inhibitors which prevent Notch activation are emerging as potent therapeutics for various inflammatory diseases, including ischemic stroke and rheumatoid arthritis. However, their indiscriminate distribution in the body causes serious side effects after systemic administration, since Notch proteins are ubiquitous receptors that play an important role in cellular functions such as differentiation, proliferation, and apoptosis. In this study, hyaluronan nanoparticles (HA-NPs) bearing a γ-secretase inhibitor (DAPT) were prepared as potential therapeutics for rheumatoid arthritis. In vivo biodistribution of the DAPT-loaded HA-NPs (DNPs), labeled with near-infrared dye, were observed using a non-invasive optical imaging system after systemic administration to a collagen-induced arthritis (CIA) mouse model. The results demonstrated that DNPs were effectively accumulated at the inflamed joint of the CIA mice. From the in vivo therapeutic efficacy tests, DNPs (1mg DAPT/kg) significantly attenuated the severity of RA induction compared to DAPT alone (2mg/kg), which was judged from clinical scores, tissue damage, and neutrophil infiltration. In addition, DNPs dramatically reduced the production of pro-inflammatory cytokines (TNF-α, IFN-γ, MCP-1, and IL-6, -12, -17) and collagen-specific auto-antibodies (IgG1 and IgG2a) in the serum of the CIA mice. These results suggest that DNPs have potential as therapeutics for rheumatoid arthritis.
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Roun
authors.initials: R
authors.lastname: Heo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Shin
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea; NanoBio Fusion Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Yung Doug
authors.initials: YD
authors.lastname: Suh
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon 440-746, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jodg@skku.edu.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon 440-746, Republic of Korea; School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea; NanoBio Fusion Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: jhpark1@skku.edu.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D004151:Dipeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry; D006820:Hyaluronic Acid / Q000737:chemistry*; D007719:Knee Joint / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*
chemical_list: D016207:Cytokines; D004151:Dipeptides; D004337:Drug Carriers; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D006820:Hyaluronic Acid; D053829:Amyloid Precursor Protein Secretases
keywords: Gamma-secretase; Hyaluronan; Nanoparticle; Rheumatoid arthritis