Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis
Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis
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DOI：
10.1016/j.ymthe.2005.07.687
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发表时间：
2006-01-01
影响因子：
12.4
通讯作者：
Muzykantov, VR
中科院分区：
文献类型：
--
作者：
Muro, S;Schuchman, EH;Muzykantov, VR
酶替代疗法是许多溶酶体贮积症的最先进治疗，其依赖于碳水化合物介导的重组酶与受体的结合，所述受体通过网格蛋白依赖性内吞作用介导溶酶体递送。重组酶的次优糖基化和一些溶酶体酶缺陷细胞中网格蛋白介导的内吞作用的缺陷限制了酶替代疗法对溶酶体疾病的递送和功效。我们探索了一种新的递送策略，利用靶向糖基化和网格蛋白非依赖性受体的纳米载体，细胞间粘附分子（ICAM）-1，一种在不同细胞类型上表达的糖蛋白，上调并在功能上参与炎症，许多溶酶体疾病的标志。我们将A型和B型尼曼-匹克病缺陷的重组人酸性鞘磷脂酶（ASM）靶向ICAM-1，方法是将该酶装载到涂有抗ICAM的纳米载体上。抗ICAM/ASM纳米载体，而非对照ASM或ASM纳米载体，以糖基化非依赖性方式经由ICAM-1结合至ICAM-1阳性细胞（活化的内皮细胞和尼曼-匹克病患者成纤维细胞）。抗ICAM/ASM纳米载体通过CAM介导的内吞作用进入细胞，绕过网格蛋白依赖性途径，并运输到溶酶体，其中递送的ASM显示稳定的活性并减轻溶酶体脂质积聚。因此，使用靶向ICAM-1的纳米载体的溶酶体酶靶向绕过失效的通路，并且可以改善酶替代疗法对溶酶体病症（例如尼曼-匹克病）的功效。
Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a g lycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.