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Site-Specific Inhibition of Glomerulonephritis Progression by Targeted Delivery of Dexamethasone to Glomerular Endothelium

Medical Biology Section (S.A.Á., J.A.A.M.K., H.I.B., P.J.Z., P.H., K.v.d.W., A.H.P., H.M., H.E.M., G.M.) and Pathology Section (H.v.G.), Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, The Netherlands; Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (E.S.); and Department of Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands (C.G.K.)

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.

Address correspondence to: S. A.Ásgeirsdóttir, Department of Pathology and Laboratory Medicine, Medical Biology Section, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: s.a.asgeirsdottir{at}med.umcg.nl

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				S. A. Asgeirsdottir, P. J. Zwiers, H. W. Morselt, H. E. Moorlag, H. I. Bakker, P. Heeringa, J. W. Kok, C. G. M. Kallenberg, G. Molema, and J. A. A. M. Kamps Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes Am J Physiol Renal Physiol, March 1, 2008; 294(3): F554 - F561. [Abstract] [Full Text] [PDF]