title: Drug targeting to monocytes and macrophages using esterase-sensitive chemical motifs.
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.
authors.affiliation: Chroma Therapeutics Ltd, Abingdon, Oxon OX14 4RY, United Kingdom.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Needham
authors.forename: Alan H
authors.initials: AH
authors.lastname: Davidson
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Bawden
authors.forename: Andrew
authors.initials: A
authors.lastname: Belfield
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Bone
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Brotherton
authors.forename: Sam
authors.initials: S
authors.lastname: Bryant
authors.forename: Michael H
authors.initials: MH
authors.lastname: Charlton
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Clark
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Davies
authors.forename: Alastair
authors.initials: A
authors.lastname: Donald
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Day
authors.forename: David
authors.initials: D
authors.lastname: Krige
authors.forename: Valérie
authors.initials: V
authors.lastname: Legris
authors.forename: Joanne
authors.initials: J
authors.lastname: McDermott
authors.forename: Yvonne
authors.initials: Y
authors.lastname: McGovern
authors.forename: Jo
authors.initials: J
authors.lastname: Owen
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Patel
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pintat
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Testar
authors.forename: Graham M A
authors.initials: GM
authors.lastname: Wells
authors.forename: David
authors.initials: D
authors.lastname: Moffat
authors.forename: Alan H
authors.initials: AH
authors.lastname: Drummond
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001168:Arthritis / Q000276:immunology; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004950:Esterases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D004952:Esters / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000596:Amino Acids; D000841:Anisomycin; D043182:Carboxylesterase; D016207:Cytokines; D004791:Enzyme Inhibitors; D004950:Esterases; D004952:Esters; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2