Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.

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TitleLysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.
Publication TypeJournal Article
Year of Publication2006
AuthorsMuro, S, Schuchman, EH, Muzykantov, VR
JournalMol Ther
Volume13
Issue1
Pagination135-41
Date Published2006 Jan
ISSN1525-0016
KeywordsAntibodies, Monoclonal, Cells, Cultured, Clathrin, Drug Delivery Systems, Endocytosis, Endothelial Cells, Fibroblasts, Glycosylation, Humans, Intercellular Adhesion Molecule-1, Lysosomes, Nanostructures, Niemann-Pick Diseases, Recombinant Proteins, Sphingomyelin Phosphodiesterase
Abstract

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 glycosylation-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.

DOI10.1016/j.ymthe.2005.07.687
Alternate JournalMol. Ther.
PubMed ID16153895
Grant ListHD 28607 / HD / NICHD NIH HHS / United States
HL/GM 71175-01 / HL / NHLBI NIH HHS / United States