ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement

J Drug Target. Nov-Dec 2017;25(9-10):786-795. doi: 10.1080/1061186X.2017.1349771. Epub 2017 Jul 14.

Abstract

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.

Keywords: ICAM-1 targeting; Niemann–Pick disease; acid sphingomyelinase; enzyme replacement therapy; fibrinogen-derived peptide; lysosomal storage diseases; polymer nanocarriers.

MeSH terms

  • Amino Acid Sequence
  • Drug Carriers / administration & dosage
  • Drug Carriers / metabolism*
  • Drug Delivery Systems / methods*
  • Fibrinogen / administration & dosage
  • Fibrinogen / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Nanoparticles / administration & dosage
  • Nanoparticles / metabolism*
  • Protein Transport / drug effects
  • Protein Transport / physiology

Substances

  • Drug Carriers
  • Intercellular Adhesion Molecule-1
  • Fibrinogen