Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease.
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 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, the delivery of (125)I-α-Gal was markedly enhanced by anti-ICAM/(125)I-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, this ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease.
Fischell Department of Bioengineering, School of Engineering, University of Maryland College Park, College Park, MD 20742, USA.
Janet
J
Hsu
Daniel
D
Serrano
Tridib
T
Bhowmick
Kishan
K
Kumar
Yang
Y
Shen
Yuan Chia
YC
Kuo
Carmen
C
Garnacho
Silvia
S
Muro
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology*; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D000519:alpha-Galactosidase / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D004337:Drug Carriers; C472766:Gb3 antigen; D018799:Intercellular Adhesion Molecule-1; D000519:alpha-Galactosidase