Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.
Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.
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DOI：
10.1016/j.jconrel.2010.10.031
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发表时间：
2011-02-10
期刊：
影响因子：
--
通讯作者：
Muro S
中科院分区：
文献类型：
--
作者：
Hsu J;Serrano D;Bhowmick T;Kumar K;Shen Y;Kuo YC;Garnacho C;Muro S
由于 α-半乳糖苷酶 A (α-Gal) 缺乏而导致的法布里病会导致三酰神经酰胺 (Gb3) 在多个组织中溶酶体积聚，尤其是在血管内皮中。尽管通过注射重组α-Gal进行酶替代疗法（ERT）可改善疾病结果，但对与危及生命的脑血管、心脏和肾脏并发症相关的血管病变的影响仍然有限。我们设计了一种策略来增强 α-Gal 向器官和内皮细胞 (EC) 的递送。我们将 α-Gal 靶向细胞间粘附分子 1 (ICAM-1)，这是一种在整个脉管系统的 EC 上表达的蛋白质，通过将该酶负载到涂有抗 ICAM（抗 ICAM/α-Gal NC）的纳米载体上。体外放射性同位素示踪显示 α-Gal 在抗 ICAM NC 上的有效负载、该制剂在储存和模型生理液体中的稳定性以及响应溶酶体环境条件的酶释放。在小鼠中，抗 ICAM/125I-α-Gal NC 在脑、肾、心脏、肝脏、肺和脾中显着增强了 125I-α-Gal 的递送，透射电子显微镜显示抗 ICAM/α-Gal NC 附着并内化到血管内皮中。荧光显微镜证明抗 ICAM/α-Gal NC 在大血管和微血管 EC 中的靶向、内吞作用和溶酶体转运，以及 Gb3 降解的显着增强。因此，ICAM-1靶向策略可能有助于提高治疗酶对法布里病的疗效。
Fabry disease due to deficiency of α-galactosidase A (α-Gal) causes lysosomal accumulation of globotriaosylceramide (Gb3) in multiple tissues and prominently in the vascular endothelium. Although enzyme replacement therapy (ERT) by injection of recombinant α-Gal improves the disease outcome, effects on the vasculopathy associated to life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance delivery of α-Gal to organs and endothelial cells (ECs). We targeted α-Gal to intercellular adhesion molecule 1 (ICAM-1), a protein expressed on ECs throughout the vasculature, by loading this enzyme on nanocarriers coated with anti-ICAM (anti-ICAM/α-Gal NCs). In vitro radioisotope tracing showed efficient loading of α-Gal on anti-ICAM NCs, stability of this formulation under storage and in model physiological fluids, and enzyme release in response to lysosome environmental conditions. In mice, delivery of 125I-α-Gal was markedly enhanced by anti-ICAM/125I-α-Gal NCs in brain, kidney, heart, liver, lung, and spleen, and transmission electron microscopy showed anti-ICAM/α-Gal NCs attached to and internalized into the vascular endothelium. Fluorescence microscopy proved targeting, endocytosis and lysosomal transport of anti-ICAM/α-Gal NCs in macro- and micro-vascular ECs, and a marked enhancement of Gb3 degradation. Therefore, ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease.
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影响因子：
4.8
作者：
Dhami, R;Schuchman, EH
通讯作者：
Schuchman, EH
影响因子：
4.6
作者：
Chittasupho, Chuda;Xie, Sheng-Xue;Baoum, Abdulgader;Yakovleva, Tatyana;Siahaan, Teruna J.;Berkland, Cory J.
通讯作者：
Berkland, Cory J.
DOI：
10.1186/1755-8417-1-6
发表时间：
2008-12-01
期刊：
PathoGenetics
影响因子：
--
作者：
Cardone, Monica;Porto, Caterina;Parenti, Giancarlo
通讯作者：
Parenti, Giancarlo
影响因子：
3.1
作者：
LEGLER, G;POHL, S
通讯作者：
POHL, S
影响因子：
19.6
作者：
Linthorst, GE;Hollak, CEM;Aerts, JMFG
通讯作者：
Aerts, JMFG