Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis through dye-functionalized lipid nanocarriers

Abstract

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 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.One-Sentence SummaryDye-functionalized liposomes allow delivery of a PI3Kγ inhibitor to hepatocytes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.Graphical AbstractTargeting PI3Kγ in hepatocytes by dye-functionalized liposomes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.

RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis

“…Lastly, the peritoneal contamination and infection model (PCI) is employed to induce bacterial sepsis, one of the leading causes of death in intensive care units. This model results in acute peritonitis associated with a strong pro-inflammatory phenotype and even systemic cytokine storm, mimicked by the LPS and cytokine mix inducing the RIPK3 expression in HepG2 cells [65,66].…”