title: Targeting, endocytosis, and lysosomal delivery of active enzymes to model human neurons by ICAM-1-targeted nanocarriers.
abstract: OBJECTIVE
  Delivery of therapeutics to neurons is paramount to treat neurological conditions, including many lysosomal storage disorders. However, key aspects of drug-carrier behavior in neurons are relatively unknown: the occurrence of non-canonical endocytic pathways (present in other cells); whether carriers that traverse the blood-brain barrier are, contrarily, retained within neurons; if neuron-surface receptors are accessible to bulky carriers compared to small ligands; or if there are differences regarding neuronal compartments (neuron body vs. neurites) pertaining said parameters. We have explored these questions using model polymer nanocarriers targeting intercellular adhesion molecule-1 (ICAM-1).
  
  
  METHODS
  Differentiated human neuroblastoma cells were incubated with anti-ICAM-coated polystyrene nanocarriers and analyzed by fluorescence microscopy.
  
  
  RESULTS
  ICAM-1 expression and nanocarrier binding was enhanced in altered (TNFα) vs. control conditions. While small ICAM-1 ligands (anti-ICAM) preferentially accessed the cell body, anti-ICAM nanocarriers bound with faster kinetics to neurites, yet reached similar saturation over time. Anti-ICAM nanocarriers were also endocytosed with faster kinetics and lower saturation levels in neurites. Non-classical cell adhesion molecule (CAM) endocytosis ruled uptake, and neurite-to-cell body transport was inferred. Nanocarriers trafficked to lysosomes, delivering active enzymes (dextranase) with substrate reduction in a lysosomal-storage disease model.
  
  
  CONCLUSIONS
  ICAM-1-targeting holds potential for intracellular delivery of therapeutics to neurons.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, 20742, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Hsu
authors.forename: Janet
authors.initials: J
authors.lastname: Hoenicka
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D003910:Dextranase / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D016464:Lysosomal Storage Diseases; D008247:Lysosomes / Q000378:metabolism*; D049329:Nanostructures / Q000737:chemistry*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004337:Drug Carriers; D018799:Intercellular Adhesion Molecule-1; D003910:Dextranase