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

Abstract

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.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Specific targeted delivery of therapeutic agents to kidneys, and even to specific renal cells in the glomeruli or the tubulointerstitium, seems feasible (442)(443)(444)(445)(446)(447) and might open the possibility of using drugs that would otherwise be limited by systemic toxicity. Such approaches may also be combined with contrast agents for non-invasive imaging allowing a ''theranostic'' strategy which is currently mainly being developed for cancer applications.…”

Antibody-Conjugated Nanoparticles for Therapeutic Applications

“…Also, anti-E-selectin ILs loaded with dexamethasone have been tested in vivo and display binding and internalization in a mouse model of skin inflammation [141]. Dexamethasone-loaded Ls conjugated with anti-E-selectin antibodies were shown to be internalized by activated endothelial cells in vitro through E-selectin-mediated endocytosis in an injury model characterized by glomerular renal inflammation [142,303]. These ILs not only show an accumulation in the inflamed kidney 3.6 times higher than non-targeted IgG Ls, but also reduce inflammatory gene expression without affecting blood glucose levels, a severe side effect of administration of free dexamethasone.…”

siRNA Delivery to the Glomerular Mesangium Using Polycationic Cyclodextrin Nanoparticles Containing siRNA

“…It remains to be determined whether the siRNA/CDP NP system can facilitate gene knockdown in mouse models of kidney disease. However, reports examining nanoparticle delivery to the diseased kidney in animal models [6,9,[32][33][34][35] suggest that nanoparticles have a higher propensity for glomerular deposition in glomerulonephritic states, likely due to increased vascular permeability and inflammation. Thus, the healthy, rather than the diseased kidney, may provide the more restrictive condition for nanoparticle delivery.…”