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.

Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer

“…Translation to the clinic will require development of strategies for manipulation of either OSM production from macrophages or OSM reception and signalling through OSMR in tumour cells. Some existing chemotherapies are under investigation for their suppressive effects on myeloid cells (Naiditch et al 2011) and new chemical and liposomal drug delivery systems that target macrophages are in development (Kelly et al 2011, Needham et al 2011. Development and clinical testing of monoclonal antibody-based therapies targeting IL6 signalling at both the ligand and the receptor level are already well advanced (Jones et al 2011), suggesting that OSM/ OSMR signalling may be a feasible therapeutic target.…”

New and emerging HDAC inhibitors for cancer treatment

“…Chemical hybrid molecules containing both HDACi activity and an additional anticancer module are under development, and while the HDACi component is relatively broad spectrum, targeting HDACs concurrent with inhibition of PI3K (CUDC-907), tyrosine kinase (CUDC-101), or topoisomerase II (daunorubicin-vorinostat), or with 1α,25-vitamin D (triciferol) for nuclear receptor targeting (92), may be of interest for particular cancer subtypes. Additionally, an esterHDACi hybrid has been developed consisting of an HDACi and an esterase-sensitive chemical motif, which is specifically hydrolyzed by human monocytes and macrophages, trapping the active drug inside the cell (93). While this technology is currently useful for the inhibition of HDAC-regulated inflammatory cytokines and the treatment of inflammatory diseases, it also provides an impetus to utilize the hybrid technology to develop more cell type-specific HDACis for use in cancer.…”

A phase I first‐in‐human study with tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with advanced haematological malignancies

“…Human monocytic cell lines (U-937, THP-1) were much more sensitive to tefinostat than non-monocytic cell lines (IC 50 , 22-62 nmol/l vs. 425-4400 nmol/l). The HL-60 cell line had c.10% of the level of hCE1 expression of that found in U-937 or THP-1 cells (Needham et al, 2011), which may explain why tefinostat has an IC 50 of <1 lmol/l for this cell line. Tefinostat was 9-and 20-fold more potent in the monocytic cell lines than the non-selective HDACi vorinostat, which showed no selectivity for monocytic cell lines.…”

“…CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE1-expressing cells, resulting in a 20-to 100-fold increase in the anti-proliferative potency of tefinostat for monocytic, over non-monocytic, tumour cells. The Esterase Sensitive Motif (ESM) technology used to design tefinostat is widely applicable and an increase in potency against monocytic tumour cell lines has been demonstrated with a variety of targets (Needham et al, 2011).…”

“…Methods for analysis of hCE1 and hCE2 activity, HDAC inhibition, inhibition of cytokine production (Needham et al, 2011) and cell proliferation assays (Krige et al, 2008) have been described previously. Protein acetylation in monocytes, granulocytes and lymphocytes from human blood was as follows: human heparinized blood (1:1) was diluted with RPMI 1640 medium.…”