Indoleamine 2,3-dioxygenase (IDO) is an immunomodulating
enzyme that is overexpressed in many
cancers with poor prognosis. IDO suppresses T cell immunity by catabolizing
tryptophan into
kynurenine (KYN), which induces apoptosis in T effector cells and enhances T regulatory cells, providing a powerful immunosuppressive mechanism in
tumors. Thus, major efforts for developing IDO inhibitors have been undertaken. Among them,
1-Methyl-l-Tryptophan (MLT) and 1-Methyl-d-Tryptophan (MDT) effectively inhibit IDO in preclinical
tumor models and the latter is under clinical evaluation. However, both MLT and MDT present poor pharmacokinetics, with the maximum serum concentration being below their 50% inhibitory concentration value. Herein, we have developed polymeric IDO inhibitors based on MLT, which can release active MLT after enzymatic degradation, toward establishing superior antitumor
immunotherapies. These
polymers were prepared by ring opening polymerization of an N-phenyl
carbamate (NPC) derivative of MLT that was synthesized by carbamylation with
diphenyl carbonate. By using ω-amino-poly(
ethylene glycol) (PEG-NH2) as the macroinitiator, we prepared amphiphilic PEG-poly(MLT) block copolymers, which self-assembled into polymeric
micelles in aqueous conditions. The PEG-poly(MLT) block copolymers could be readily degraded by
chymotrypsin and the
micelles were able to reduce the levels of KYN in activated macrophages. These results provide a strong rationale for pursuing MLT-based polymeric
micelles as
tumor-targeted
prodrug systems.