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PEG-Poly(1-Methyl-l-Tryptophan)-Based Polymeric Micelles as Enzymatically Activated Inhibitors of Indoleamine 2,3-Dioxygenase

Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
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Nanomaterials 2019, 9(5), 719; https://doi.org/10.3390/nano9050719
Received: 17 April 2019 / Revised: 30 April 2019 / Accepted: 1 May 2019 / Published: 9 May 2019
(This article belongs to the Special Issue Polymeric Micelles and Their Application in Nanomedicine)
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Abstract

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. View Full-Text
Keywords: polymeric micelles; indoleamine 2,3-dioxygenase; 1-Methyl-Tryptophan; enzymatic degradation; immunotherapy polymeric micelles; indoleamine 2,3-dioxygenase; 1-Methyl-Tryptophan; enzymatic degradation; immunotherapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Huang, G.L.; Tao, A.; Miyazaki, T.; Khan, T.; Hong, T.; Nakagawa, Y.; Cabral, H. PEG-Poly(1-Methyl-l-Tryptophan)-Based Polymeric Micelles as Enzymatically Activated Inhibitors of Indoleamine 2,3-Dioxygenase. Nanomaterials 2019, 9, 719.

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