Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice

Mol Ther. 2017 Jul 5;25(7):1686-1696. doi: 10.1016/j.ymthe.2017.05.014. Epub 2017 Jun 9.


Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Here, using polystyrene and poly(lactic-co-glycolic acid) nanocarriers, we optimized lung delivery by varying enzyme dose and nanocarrier concentration, verified endocytosis and lysosomal trafficking in vivo, and evaluated delivered activity and effects. Raising the enzyme load of nanocarriers progressively increased absolute enzyme delivery to all lung, liver, and spleen, over the naked enzyme. Varying nanocarrier concentration inversely impacted lung versus liver and spleen uptake. Mouse intravital and postmortem examination verified endocytosis, transcytosis, and lysosomal trafficking using nanocarriers. Compared to naked enzyme, nanocarriers increased enzyme activity in organs and reduced lung sphingomyelin storage and macrophage infiltration. Although old mice with advanced disease showed reactivity (pulmonary leukocyte infiltration) to injections, including buffer without carriers, antibody, or enzyme, younger mice with mild disease did not. We conclude that anti-ICAM nanocarriers may result in effective lung enzyme therapy using low enzyme doses.

Keywords: ICAM-1 targeting; acid sphingomyelinase deficiency; enzyme replacement therapy; polymer nanocarriers; pulmonary effects; type B Niemann-Pick disease.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / metabolism
  • Biological Transport
  • Drug Carriers*
  • Drug Compounding
  • Endocytosis
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lactic Acid / chemistry
  • Lactic Acid / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Lung / drug effects
  • Lung / enzymology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry*
  • Niemann-Pick Disease, Type B / enzymology
  • Niemann-Pick Disease, Type B / genetics
  • Niemann-Pick Disease, Type B / pathology
  • Niemann-Pick Disease, Type B / therapy*
  • Polyglycolic Acid / chemistry
  • Polyglycolic Acid / metabolism
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polystyrenes / chemistry
  • Polystyrenes / metabolism
  • Sphingomyelin Phosphodiesterase / chemistry
  • Sphingomyelin Phosphodiesterase / deficiency
  • Sphingomyelin Phosphodiesterase / pharmacology*
  • Sphingomyelins / metabolism
  • Spleen / drug effects
  • Spleen / enzymology
  • Spleen / pathology


  • Antibodies, Monoclonal
  • Drug Carriers
  • Polystyrenes
  • Sphingomyelins
  • Intercellular Adhesion Molecule-1
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Sphingomyelin Phosphodiesterase