Hyaluronan nanoparticles bearing gamma-secretase inhibitor: In vivo therapeutic effects on rheumatoid arthritis

Abstract

gamma-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 gamma-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 (1 mg DAPT/kg) significantly attenuated the severity of RA induction compared to DAPT alone (2 mg/kg), which was judged from clinical scores, tissue damage, and neutrophil infiltration. In addition, DNPs dramatically reduced the production of pro-inflammatory cytokines (TNF-alpha, IFN-gamma, 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. (C) 2014 Elsevier B.V. All rights reserved.