Drug targeting to monocytes and macrophages using esterase-sensitive chemical motifs

J Pharmacol Exp Ther. 2011 Oct;339(1):132-42. doi: 10.1124/jpet.111.183640. Epub 2011 Jul 21.

Abstract

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Anisomycin / pharmacology
  • Arthritis / immunology
  • Carboxylesterase / antagonists & inhibitors
  • Carboxylesterase / chemistry
  • Carboxylesterase / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / biosynthesis
  • Cytokines / blood
  • Cytokines / genetics
  • Drug Delivery Systems / methods*
  • Enzyme Inhibitors / pharmacology
  • Esterases / antagonists & inhibitors*
  • Esterases / chemistry*
  • Esterases / genetics
  • Esters / metabolism
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Transgenic
  • Monocytes / drug effects*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / blood
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Amino Acids
  • Cytokines
  • Enzyme Inhibitors
  • Esters
  • HSP90 Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Anisomycin
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Esterases
  • Carboxylesterase