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

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 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.

The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation

“…In infection driven-inflammation and related liver failure, Phosphoinositide 3-kinase- (PI3K ) signaling has been suggested as a pacemaker for intrahepatic excretory liver failure in mice and humans (Recknagel et al 2012 ; Press et al 2021 ). PI3K -knockout mice and mice treated with the PI3K inhibitor AS605240 did not develop liver failure but suffered from immunological side effects (Press et al 2021 ). PI3K stimulates the phosphorylation and activation of protein kinase B (Akt), finally activating mTOR.…”

“…Studies further depict that FXR mediates pro-survival signals in hepatocytes by inhibiting the biosynthesis of bile acids, reducing the uptake of bile salts, and increasing their export through BSEP (Gomez-Ospina et al 2016 ). In infection driven-inflammation and related liver failure, PI3K signaling had been suggested to be a pacemaker for intrahepatic excretory liver failure in mice and humans (Recknagel et al 2012 ; Press et al 2021 ). PI3K knockout mice and mice treated with the PI3K inhibitor AS605240 did not develop liver failure but suffered from immunological side effects (Table 2 ).…”

“…PI3K knockout mice and mice treated with the PI3K inhibitor AS605240 did not develop liver failure but suffered from immunological side effects (Table 2 ). However, PI3K knockout and AS605240 mice showed a neutrophil dysfunction associated with a cytokine storm that resulted in inadequate bacterial clearance and loss of any survival benefit (Recknagel et al 2012 ; Press et al 2021 ). Formulations resulting in an enrichment of AS605240 in hepatocytes reduced the immunological side effects without affecting the protective effects on liver function, ultimately increasing the survival rates of these mice (Press et al 2021 ).…”

“…However, PI3K knockout and AS605240 mice showed a neutrophil dysfunction associated with a cytokine storm that resulted in inadequate bacterial clearance and loss of any survival benefit (Recknagel et al 2012 ; Press et al 2021 ). Formulations resulting in an enrichment of AS605240 in hepatocytes reduced the immunological side effects without affecting the protective effects on liver function, ultimately increasing the survival rates of these mice (Press et al 2021 ). While this approach seems promising, further studies are needed to validate these findings and translate such targeted therapies into clinical trials.…”

The liver-gut-axis: initiator and responder to sepsis

“…Sepsis and multiorgan failure represent common conditions of critically ill patients in ICUs, responsible for immense global mortality and economic burden [ 36 ]. Most ICU patients receive antibiotics, causing depletion of commensal gut bacteria [ 37 ], enrichment of opportunistic pathogens [ 8 ] and disturbance of immune response and physiological activity, which in turn influence organ functions such as bile production in the liver [ 38 , 39 ]. Perturbation of the gut microbiome even with a short antibiotic administration can persist for months [ 40 ], whereas broad-spectrum antibiotic usage can cause extreme and long-lasting disbalance with an unknown impact on the recovery of critically ill patients [ 29 ].…”