Nanoparticle-mediated drug delivery for inflammatory Arthritis

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Project Summary Inflammatory Arthritis (IA) is an autoimmune disease characterized by chronic erosive arthritis and systemic lesions of multiple organs. The major types of IA include Gout, Psoriatic arthritis (PA), and Rheumatoid Arthritis (RA). RA pathogenesis is based on complex mutual effects of genetic an acquired defects of immune balance between regulatory and inflammatory responses1. Regulatory T cells (Treg) and Myeloid-derived suppressor cells (MDSCs) are typical immune-regulators, and defects or malfunction of these cells contributes to the pathogenesis of RA. SH2-containing inositol-5'-phosphatase- 1 (SHIP1) is an enzyme with phosphatase activity, which controls PI3K initiated signaling. We found that temporal inhibition of SHIP1 by 3-α-Aminocholestane (3AC) would suppress the initiation and progression of experimental mouse arthritis (CIA), and the expansion and maintenance of regulatory cells for an extended period of time would be required for the prevention of severe inflammatory damages. Based on our preliminary studies, we hypothesize that temporal inhibition by NPs containing SHIP1 inhibitor (3AC-NPs) not only expand cell number, but also enhance regulatory cell function. Also, regional suppression of SHIP1 in inflammation sites through IA injection could relieve the arthritic symptom in CIA mice. The primary objective of the current project through a collaboration with Rhode Island College and Rhode Island Hospital is to develop a potential therapeutic strategy for arthritic inflammation using SHIP1 inhibitor and Nanoparticles (NPs). Through this collaboration we aim to generate 3AC-NPs and to examine the anti-inflammatory functions in RA mouse model as well as train undergraduates in state-of-the-art methods of drug delivery and disease treatment. We expect that that the administration of 3AC-NPs results in reduced inflammatory responses at synovial tissues. Our long-term goal is to develop novel strategies for treatment of inflammatory diseases, as well as prepare undergraduates students for careers in medicine, biomedical engineering, and pharmaceutical industry.