TY - JOUR
T1 - Modularly Designed Peptide Nanoprodrug Augments Antitumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2,3-Dioxygenase
AU - Han, Xuexiang
AU - Cheng, Keman
AU - Xu, Ying
AU - Wang, Yazhou
AU - Min, Huan
AU - Zhang, Yinlong
AU - Zhao, Xiao
AU - Zhao, Ruifang
AU - Anderson, Gregory J.
AU - Ren, Lei
AU - Nie, Guangjun
AU - Li, Yiye
N1 - Funding Information:
This work was supported by the grants from the National Basic Research Plan of China (2018YFA0208900, 2016YFA0201600), the National Natural Science Foundation of China (31571021), the Innovation Group of the National Natural Science Foundation of China (11621505), the Frontier Research Program of the Chinese Academy of Sciences (QYZDJ-SSW-SLH022), and the Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, CAS.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/2/5
Y1 - 2020/2/5
N2 - The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade in vivo. Overall, this study provides a promising paradigm of combinatorial normalization immunotherapy by exploiting a targeted IDO nanoinhibitor to augment the antitumor immunity of checkpoint inhibitors.
AB - The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade in vivo. Overall, this study provides a promising paradigm of combinatorial normalization immunotherapy by exploiting a targeted IDO nanoinhibitor to augment the antitumor immunity of checkpoint inhibitors.
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U2 - 10.1021/jacs.9b12232
DO - 10.1021/jacs.9b12232
M3 - Article
C2 - 31944687
AN - SCOPUS:85079021786
SN - 0002-7863
VL - 142
SP - 2490
EP - 2496
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 5
ER -