Targeting intracellular drugs to macrophages using esterase-sensitive motif (ESM) technology: Application to anti-cancer

5612 Tumor-associated macrophages (TAMs) are now thought to have the potential to facilitate, rather than restrict, the development of human cancer. The availability of agents that reliably alter the function of TAMs would allow a thorough investigation of their role in cancer and potentially provide a novel therapeutic approach. ESM technology uses the carboxylesterase, hCE-1, which is only found in monocyte/macrophages, to drive the selective delivery of many classes of drugs. The technology involves the use of specifically designed amino acid ester motifs that are selectively hydrolysed intracellularly by hCE-1 to charged amino acid derivatives which accumulate only in monocytes and macrophages. These motifs can be incorporated into a range of agents and a series of drug types have been synthesised targeting enzymes such as histone deacetylase, p38 MAP kinase, PI-3 kinase, dihydrofolate reductase and IκB-2. Qualitatively similar data, in terms of macrophage-targeting, are found irrespective of the parent molecule. In many cases, the amino acid ester derivative is significantly less effective (