Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes.
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.
Asgeirsdóttir
Sigrídur A
SA
Department of Pathology & Laboratory Medicine, Medical Biology Section, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. s.a.asgeirsdottir@med.umcg.nl
Zwiers
Peter J
PJ
Morselt
Henriëtte W
HW
Moorlag
Hendrik E
HE
Bakker
Hester I
HI
Heeringa
Peter
P
Kok
Jan Willem
JW
Kallenberg
Cees G M
CG
Molema
Grietje
G
Kamps
Jan A A M
JA
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000906:Antibodies / Q000378:metabolism; D002460:Cell Line; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D019040:E-Selectin / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply; D007678:Kidney Glomerulus / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D000906:Antibodies; D019040:E-Selectin; D007074:Immunoglobulin G; D008081:Liposomes; D003907:Dexamethasone