Development of novel liver-targeting glucocorticoid prodrugs.

Background: Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC's various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis. Methods: A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture. Results: CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice. Conclusions: CA-CB-DEX demonstrated good hepatocyte-selectivity