Submitted on August 20, 2007
Accepted on December 20, 2007
Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes
Sigridur A. Asgeirsdottir1*, Peter J. Zwiers1, Henriette W. Morselt1, Hendrik E. Moorlag2, Hester I. Bakker2, Peter Heeringa2, Jan Willem Kok3, Cees G. Kallenberg4, Grietje Molema1, and Jan A. Kamps1
1 Pathology and Laboratorium Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
2 Groningen, Netherlands; Pathology and Laboratorium Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
3 Cell Biology, Section Membrane Cell Biology, University Medical Center Groningen, Groningen, Netherlands
4 Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
* To whom correspondence should be addressed. E-mail: s.a.asgeirsdottir{at}med.umcg.nl.
E-selectin directed targeted drug delivery was analyzed in anti-glomerular basement membrane (anti-GBM) glomerulonephritis. AbEsel 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 AbEsel liposomes to glomeruli after intravenous administration. Accumulation of AbEsel liposomes in the kidney was 3.6 times higher than non-targeted 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 AbEsel liposomes co-localized 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 AbEsel liposomes reduced glomerular endothelial expression of P-selectin, E-selectin and VCAM-1 by 60 - 70%. The expression of these genes was not modulated in endothelial cells in non-targeted 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.
