5 years ago

Immunomodulatory Therapy of Inflammatory Liver Disease Using Selectin-Binding Glycopolymers

Immunomodulatory Therapy of Inflammatory Liver Disease Using Selectin-Binding Glycopolymers
Frank Tacke, Matthias Barz, Christian Trautwein, Matthias Bartneck, Rudolf Zentel, Christopher Thorsten Schlößer, Twan Lammers
Immunotherapies have the potential to significantly advance treatment of inflammatory disease and cancer, which are in large part driven by immune cells. Selectins control the first step in immune cell adhesion and extravasation, thereby guiding leukocyte trafficking to tissue lesions. We analyzed four different highly specific selectin-binding glycopolymers, based on linear poly(2-hydroxypropyl)-methacrylamide (PHPMA) polymers. These glycopolymers contain either the tetrasaccharide sialyl-LewisX (SLeX) or the individual carbohydrates fucose, galactose, and sialic acids mimicking the complex SLeX binding motive. The glycopolymers strongly bind to primary human macrophages, without activating them, and also to primary human blood leukocytes, but poorly to fibroblasts and endothelial cells in vitro. After intravenous injection in mice, all glycopolymers accumulated in the liver without causing hepatotoxicity. The glycosylated binder most potently targeted resident hepatic macrophages (Kupffer cells) and protected mice from acute toxic liver injury in the two different experimental models, carbon tetrachloride (CCl4) or Concanavalin A (ConA)-based hepatitis. Its sulfated counterpart, on the other hand, induced a decrease in infiltrating and resident macrophages, increased T helper cells, and aggravated immune-mediated liver injury. We demonstrate that, in the context of selectin-binding glycopolymers, minor modifications strongly impact leukocyte influx and macrophage activation, thereby ameliorating or aggravating liver inflammation depending on the underlying immunopathology. The nonsulfated random glycopolymer is a promising candidate for the treatment of inflammatory disease. The modulation of hepatic immune cells by selectin-binding glycopolymers might breach the immunosuppressive hepatic microenvironment and could improve efficacy of immunotherapies for inflammatory disease and cancer.

Publisher URL: http://dx.doi.org/10.1021/acsnano.7b04630

DOI: 10.1021/acsnano.7b04630

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