Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes
Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes
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DOI：
10.1152/ajprenal.00391.2007
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发表时间：
2008-03-01
影响因子：
4.2
通讯作者：
Kamps, Jan A. A. M.
中科院分区：
文献类型：
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作者：
Asgeirdottir, Sigridur A.;Zwiers, Peter J.;Kamps, Jan A. A. M.
分析了e -选择素在抗肾小球基底膜肾小球肾炎中的靶向给药作用。结合抗e -选择素抗体的脂质体（Ab（Esel）脂质体）在体外通过e -选择素介导的内吞作用被活化的内皮细胞内化。在小鼠肾小球肾炎发病时，e -选择素在肾小球内皮细胞上表达，导致静脉给药后Ab（Esel）脂质体归巢到肾小球。肾脏中Ab（Esel）脂质体的蓄积比非靶向IgG脂质体高3.6倍，而两种脂质体在肝脏和脾脏以及心脏和肺部的蓄积是相当的。在肾小球中，Ab（Esel）脂质体与内皮细胞标志物CD31共定位。激光显微解剖的小动脉、肾小球和毛细血管后小静脉的定量RT-PCR分析表明，通过Ab（Esel）脂质体靶向递送地塞米松可降低肾小球内皮中p -选择素、e-选择素和血管细胞粘附分子-1的表达60-70%。这些基因的表达在非靶向肾微血管内皮细胞中不受调节。疾病开始时肾小球内皮活化降低，第7天蛋白尿减少。本研究证明了针对疾病诱导的微血管内皮细胞表位的血管床特异性药物递送作为肾小球肾炎治疗策略的潜力。
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.