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Enhanced endothelial delivery and biochemical effects of ?-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.

ABSTRACT: Fabry disease, due to the deficiency of ?-galactosidase A (?-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 ?-Gal improves the disease outcome, the effects on the vasculopathy associated with life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance the delivery of ?-Gal to organs and endothelial cells (ECs). We targeted ?-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/?-Gal NCs). In vitro radioisotope tracing showed efficient loading of ?-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, the delivery of (125)I-?-Gal was markedly enhanced by anti-ICAM/(125)I-?-Gal NCs in brain, kidney, heart, liver, lung, and spleen, and transmission electron microscopy showed anti-ICAM/?-Gal NCs attached to and internalized into the vascular endothelium. Fluorescence microscopy proved targeting, endocytosis and lysosomal transport of anti-ICAM/?-Gal NCs in macro- and micro-vascular ECs and a marked enhancement of Gb3 degradation. Therefore, this ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease.

SUBMITTER: Hsu J

PROVIDER: S-EPMC3073729 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.

Hsu Janet J Serrano Daniel D Bhowmick Tridib T Kumar Kishan K Shen Yang Y Kuo Yuan Chia YC Garnacho Carmen C Muro Silvia S

Journal of controlled release : official journal of the Controlled Release Society 20101101 3

Fabry disease, due to the 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, the effects on the vasculopathy associated with life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance the delivery of α-Gal to organs an ...[more]

PMID: 21047542

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Project description:Delivery of drugs into the endothelium by nanocarriers targeted to endothelial determinants may improve treatment of vascular maladies. This is the case for intercellular adhesion molecule 1 (ICAM-1), a glycoprotein overexpressed on endothelial cells (ECs) in many pathologies. ICAM-1-targeted nanocarriers bind to and are internalized by ECs via a non-classical pathway, CAM-mediated endocytosis. In this work we studied the effects of endothelial adaptation to physiological flow on the endocytosis of model polymer nanocarriers targeted to ICAM-1 (anti-ICAM/NCs, ~180 nm diameter). Culturing established endothelial-like cells (EAhy926 cells) and primary human umbilical vein ECs (HUVECs) under 4 dyn/cm(2) laminar shear stress for 24 h resulted in flow adaptation: cell elongation and formation of actin stress fibers aligned to the flow direction. Fluorescence microscopy showed that flow-adapted cells internalized anti-ICAM/NCs under flow, although at slower rate versus non flow-adapted cells under static incubation (~35% reduction). Uptake was inhibited by amiloride, whereas marginally affected by filipin and cadaverine, implicating that CAM-endocytosis accounts for anti-ICAM/NC uptake under flow. Internalization under flow was more modestly affected by inhibiting protein kinase C, which regulates actin remodeling during CAM-endocytosis. Actin recruitment to stress fibers that maintain the cell shape under flow may delay uptake of anti-ICAM/NCs under this condition by interfering with actin reorganization needed for CAM-endocytosis. Electron microscopy revealed somewhat slow, yet effective endocytosis of anti-ICAM/NCs by pulmonary endothelium after i.v. injection in mice, similar to that of flow-adapted cell cultures: ~40% (30 min) and 80% (3 h) internalization. Similar to cell culture data, uptake was slightly faster in capillaries with lower shear stress. Further, LPS treatment accelerated internalization of anti-ICAM/NCs in mice. Therefore, regulation of endocytosis of ICAM-1-targeted nanocarriers by flow and endothelial status may modulate drug delivery into ECs exposed to different physiological (capillaries vs. arterioles/venules) or pathological (ischemia, inflammation) levels and patterns of blood flow.

Dataset Information

Enhanced endothelial delivery and biochemical effects of ?-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.

Publications

Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.

Similar Datasets

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