TY - JOUR
T1 - Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
AU - Cheng, Keman
AU - Ding, Yanping
AU - Zhao, Ying
AU - Ye, Shefang
AU - Zhao, Xiao
AU - Zhang, Yinlong
AU - Ji, Tianjiao
AU - Wu, Huanhuan
AU - Wang, Bin
AU - Anderson, Gregory J.
AU - Ren, Lei
AU - Nie, Guangjun
N1 - Funding Information:
We thank Professor Hubing Shi from Sichuan University for critical reading of the manuscript. This work was supported by the grants from the National Basic Research Plan of China (2018YFA020035), the National Natural Science Foundation of China (U1505228, 31671023, 31700864, 31571021, 11621505), Beijing Natural Science Foundation (7174333), and the Key Research Program of Frontier Sciences, CAS (QYZDJ-SSW-SLH022).
Publisher Copyright:
© 2018 American Chemical Society.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/5/9
Y1 - 2018/5/9
N2 - Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.
AB - Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.
KW - cancer immunotherapy
KW - controllable drug release
KW - dual-responsive
KW - dual-targeted
KW - peptide self-assembly
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U2 - 10.1021/acs.nanolett.8b01071
DO - 10.1021/acs.nanolett.8b01071
M3 - Article
C2 - 29683683
AN - SCOPUS:85046460664
VL - 18
SP - 3250
EP - 3258
JO - Nano Letters
JF - Nano Letters
SN - 1530-6984
IS - 5
ER -