Chimeric protein and nano-construct for tissue-retained enzyme to locally suppress inflammation
June 5-9, 2018
There is considerable need for new retention strategies of immunomodulatory biologics for localized suppression of inflammation. We developed a chimeric protein as a well as a self-assembled nano-construct incorporating novel approaches for both retention and suppression to induce potent, confined metabolic programming. Immunosuppressive indoleamine 2,3 dioxygenase (IDO), which depletes tryptophan through the kynurenine pathway, was fused to Galectin 3 (Gal3), which binds extracellular glycans and provides tissue anchoring. Using a luciferase-Gal3 fusion reporter, tissue retention was prolonged to ~6 d whereas native luciferase is not retained and undetectable by 24 h. IDO-Gal3 injected subcutaneously controlled local LPS-challenged tissue inflammation. Furthermore, subgingival injection suppressed periodontal disease (PD) in a polymicrobial challenged mouse model. Multiplex analysis of gingival tissue revealed decreased inflammatory (IL-1β, IL-12p70, KC, IP10, MCP1, MIP2) and increased anti-inflammatory (IL-10, TGFβ3) proteins, indicating a shift toward homeostasis. Animals treated with IDO-Gal3 also showed significant decrease in bone loss commonly associated with PD, as determined by µCT analysis.
Benjamin Keselowsky, Evelyn Bracho-Sanchez, Gregory A. Hudalla, Sabrina Freeman, Antonietta Restuccia, Margaret M. Fettis, Mark A. Wallet, Fernanda Rocha, and Shannon M. Wallet, "Chimeric protein and nano-construct for tissue-retained enzyme to locally suppress inflammation" in "Nanotechnology in Medicine II: Bridging Translational in vitro and in vivo Interfaces", Millicent Sullivan, PhD, University of Delaware, USA Josué Sznitman, Dr. Sc., Technion-Israel Institute of Technology, Israel Lola Eniola-Adefeso, PhD, University of Michigan, USA Srivatsan Kidambi, PhD, University of Nebraska - Lincoln, USA Eds, ECI Symposium Series, (2018). http://dc.engconfintl.org/nanotech_med_ii/36