Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis

in: EMBO Molecular Medicine (2021)
Press, Adrian T.; Babic, Petra; Hoffmann, Bianca; Müller, Tina; Foo, Wanling; Hauswald, Walter; Benecke, Kay-Jovanna; Beretta, Martina; Cseresnyes, Zoltan; Hoeppener, Stephanie; Nischang, Ivo; Coldewey, Sina M.; Gräler, Markus H.; Bauer, Reinhard; Gonnert, Falk A.; Gaßler, Nikolaus; Wetzker, Reinhard; Figge, Marc Thilo; Schubert, Ulrich S.; Bauer, Michael
Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

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