Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy.

Abstract

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.

• Authors: Keman Cheng, Yanping Ding, Ying Zhao, Shefang Ye, Xiao Zhao, Yinlong Zhang, Tianjiao Ji, Huanhuan Wu, Bin Wang, Gregory J Anderson, Lei Ren, Guangjun Nie
• Journal: Nano letters (Nano Lett) Vol. 18 Issue 5 Pg. 3250-3258 (05 09 2018) ISSN: 1530-6992 [Electronic] United States
• PMID: 29683683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-cyclohexyl-2-(5H-imidazo(5,1-a)isoindol-5-yl)ethanol
• B7-H1 Antigen
• Cd274 protein, mouse
• Delayed-Action Preparations
• Imidazoles
• Isoindoles
• Peptides

Topics

• Animals
• B7-H1 Antigen (antagonists & inhibitors)
• Delayed-Action Preparations (chemistry)
• Drug Delivery Systems
• Imidazoles (administration & dosage, therapeutic use)
• Immunotherapy
• Isoindoles (administration & dosage, therapeutic use)
• Melanoma (therapy)
• Mice
• Mice, Nude
• Nanoparticles (chemistry)
• Peptides (administration & dosage, therapeutic use)
• Tumor Microenvironment (drug effects)