Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis |
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| Institution: | 1. Institute for Biomedical Sciences, USA;2. Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA;3. Veterans Affair Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA;4. Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA;1. Department of Rheumatology, Westmead Hospital, Sydney, Australia;2. Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia;3. Department of Nuclear Medicine & PET Westmead Hospital, Sydney, Australia;4. CSIRO Molecular & Health Technologies, Sydney, Australia;1. School of Life Sciences, Jilin University, Changchun, China;2. Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA;1. Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea;2. KU-KIST School, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea;3. School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea;4. School of Chemical Engineering, Sungkyunkwan University, Suwan 440-746, Republic of Korea.;5. School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.;1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan;2. Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshidaushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan |
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| Abstract: | In this study, we have shown for the first time the effectiveness of a non-viral gene transfection strategy to re-polarize macrophages from M1 to M2 functional sub-type for the treatment of rheumatoid arthritis (RA). An anti-inflammatory (IL-10) cytokine encoding plasmid DNA was successfully encapsulated into non-condensing alginate based nanoparticles and the surface of the nano-carriers was modified with tuftsin peptide to achieve active macrophage targeting. Enhanced localization of tuftsin-modified alginate nanoparticles was observed in the inflamed paws of arthritic rats upon intraperitoneal administration. Importantly, targeted nanoparticle treatment was successful in reprogramming macrophage phenotype balance as ∼66% of total synovial macrophages from arthritic rats treated with the IL-10 plasmid DNA loaded tuftsin/alginate nanoparticles were in the M2 state compared to ∼9% of macrophages in the M2 state from untreated arthritic rats. Treatment significantly reduced systemic and joint tissue pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression and prevented the progression of inflammation and joint damage as revealed by magnetic resonance imaging and histology. Treatment enabled animals to retain their mobility throughout the course of study, whereas untreated animals suffered from impaired mobility. Overall, this study demonstrates that targeted alginate nanoparticles loaded with IL-10 plasmid DNA can efficiently re-polarize macrophages from an M1 to an M2 state, offering a novel treatment paradigm for treatment of chronic inflammatory diseases. |
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| Keywords: | IL-10 gene therapy Macrophage repolarization Inflammation Rheumatoid arthritis Alginate nanoparticles Targeted delivery |
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