RT Journal Article
SR Electronic
T1 Drug Targeting to Monocytes and Macrophages Using Esterase-Sensitive Chemical Motifs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 132
OP 142
DO 10.1124/jpet.111.183640
VO 339
IS 1
A1 Lindsey A. Needham
A1 Alan H. Davidson
A1 Lindsay J. Bawden
A1 Andrew Belfield
A1 Elisabeth A. Bone
A1 Deborah H. Brotherton
A1 Sam Bryant
A1 Michael H. Charlton
A1 Vanessa L. Clark
A1 Stephen J. Davies
A1 Alastair Donald
A1 Francesca A. Day
A1 David Krige
A1 Valérie Legris
A1 Joanne McDermott
A1 Yvonne McGovern
A1 Jo Owen
A1 Sanjay R. Patel
A1 Stéphane Pintat
A1 Richard J. Testar
A1 Graham M. A. Wells
A1 David Moffat
A1 Alan H. Drummond
YR 2011
UL http://jpet.aspetjournals.org/content/339/1/132.abstract
AB 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.