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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 294/3/F554    most recent 00391.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ásgeirsdóttir, S. A. Articles by Kamps, J. A. A. M. Search for Related Content PubMed PubMed Citation Articles by Ásgeirsdóttir, S. A. Articles by Kamps, J. A. A. M.

Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded Ab_Esel liposomes

¹Department of Pathology and Laboratory Medicine, Medical Biology Section, ²Department of Cell Biology, Section of Membrane Cell Biology, and ³Department of Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Submitted 20 August 2007 ; accepted in final form 20 December 2007

E-selectin-directed targeted drug delivery was analyzed in anti-glomerular basement membrane glomerulonephritis. Liposomes conjugated with anti-E-selectin antibodies (Ab_Esel liposomes) were internalized by activated endothelial cells in vitro through E-selectin-mediated endocytosis. At the onset of glomerulonephritis in mice, E-selectin was expressed on glomerular endothelial cells, which resulted in homing of Ab_Esel liposomes to glomeruli after intravenous administration. Accumulation of Ab_Esel liposomes in the kidney was 3.6 times higher than nontargeted IgG liposomes, whereas the accumulation of both liposomes in the clearance organs liver and spleen and in heart and lungs was comparable. In glomeruli, the Ab_Esel liposomes colocalized with the endothelial cell marker CD31. Quantitative RT-PCR analysis of laser-microdissected arterioles, glomeruli, and postcapillary venules demonstrated that targeted delivery of dexamethasone by Ab_Esel liposomes reduced glomerular endothelial expression of P-selectin, E-selectin, and vascular cell adhesion molecule-1 by 60–70%. The expression of these genes was not modulated in endothelial cells in nontargeted renal microvasculatures. Decrease of glomerular endothelial activation at disease onset was followed by reduced albuminuria at day 7. This study demonstrates the potential of vascular bed-specific drug delivery aimed at disease-induced epitopes on the microvascular endothelial cells as a therapeutic strategy for glomerulonephritis.

glomerular endothelial cells; antiglomerular basement membrane disease; targeted interference; adhesion molecules; vascular gene expression