ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement.
Enzyme replacement is a viable treatment for diseases caused by genetic deficiency of lysosomal enzymes. However, suboptimal access of enzymes to target sites limits this strategy. Polymer nanocarriers (NCs) coated with antibody against intercellular adhesion molecule 1 (ICAM-1), a protein overexpressed on most cells under disease states, enhanced biodistribution and lysosomal delivery of these therapeutics. Whether this can be achieved using more biocompatible ICAM-1-targeting moieties is unknown, since intracellular uptake via this route is sensitive to the receptor epitope being targeted. We examined this using polymer NCs coated with an ICAM-1-targeting peptide derived from the fibrinogen sequence. Scrambled-sequence peptide and anti-ICAM were used as controls. NCs carried acid sphingomyelinase (ASM), used for treatment of type B Niemann-Pick disease, and fluorescence microscopy was employed to examine cellular performance. Peptide-coated/enzyme NCs efficiently targeted ICAM-1 (22-fold over non-specific counterparts; Bmax ∼180 NCs/cell; t1/2 ∼28 min), recognised human and mouse cells (1.2- to 0.7-fold binding vs. antibody/enzyme NCs), were efficiently endocytosed (71% at 1 h chase), and trafficked to lysosomes (30--45% of internalised NCs; 2 h chase). This restored lysosomal levels of sphingomyelin and cholesterol within 5 h chase (∼95% reduction over disease levels), similar to antibody-enzyme NCs. This fibrinogen-derived ICAM-1-targeting peptide holds potential for lysosomal enzyme replacement therapy.
['Garnacho|Carmen|C|', 'Muro|Silvia|S|']
D000595:Amino Acid Sequence D004337:Drug Carriers D016503:Drug Delivery Systems D005340:Fibrinogen D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D018799:Intercellular Adhesion Molecule-1 D042541:Intracellular Space D008247:Lysosomes D053758:Nanoparticles D021381:Protein Transport
ICAM-1 targeting polymer nanocarriers fibrinogen-derived peptide acid sphingomyelinase enzyme replacement therapy Niemann–Pick disease lysosomal storage diseases