Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium

Mol Pharmacol. 2007 Jul;72(1):121-31. doi: 10.1124/mol.107.034140. Epub 2007 Apr 23.

Abstract

Glomerulonephritis represents a group of renal diseases with glomerular inflammation as a common pathologic finding. Because of the underlying immunologic character of these disorders, they are frequently treated with glucocorticoids and cytotoxic immunosuppressive agents. Although effective, use of these compounds has limitations as a result of toxicity and systemic side effects. In the current study, we tested the hypothesis that targeted delivery of dexamethasone (dexa) by immunoliposomes to activated glomerular endothelium decreases renal injury but prevents its systemic side effects. E-selectin was chosen as a target molecule based on its disease-specific expression on activated glomerular endothelium in a mouse anti-glomerular basement membrane glomerulonephritis. Site-selective delivery of Ab(Esel) liposome-encapsulated dexamethasone strongly reduced glomerular proinflammatory gene expression without affecting blood glucose levels, a severe side effect of administration of free dexamethasone. Dexa-Ab(Esel) liposomes reduced renal injury as shown by a reduction of blood urea nitrogen levels, decreased glomerular crescent formation, and down-regulation of disease-associated genes. Immunoliposomal drug delivery to glomerular endothelium presents a powerful new strategy for treatment of glomerulonephritis to sustain efficacy and prevent side effects of potent anti-inflammatory drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dexamethasone / administration & dosage*
  • Disease Progression
  • E-Selectin / immunology*
  • Endothelium, Vascular / drug effects*
  • Female
  • Glomerular Basement Membrane / immunology
  • Glomerulonephritis / drug therapy*
  • Immunoglobulin G / administration & dosage*
  • Kidney Glomerulus / drug effects*
  • Liposomes
  • Mice
  • Mice, Inbred C57BL
  • Vascular Cell Adhesion Molecule-1 / biosynthesis

Substances

  • E-Selectin
  • Immunoglobulin G
  • Liposomes
  • Vascular Cell Adhesion Molecule-1
  • Dexamethasone