A Three-In-One Assembled Nanoparticle Containing Peptide-Radio-Sensitizer Conjugate and TLR7/8 Agonist Can Initiate the Cancer-Immunity Cycle to Trigger Antitumor Immune Response.

Abstract

Radiotherapy (RT) has been shown to cause immunogenic cell death (ICD) of cancer cells, which promote the release of tumor-associated antigens, and trigger the cancer-immunity cycle (CIC). However, ICD induced by RT usually does not occur in hypoxic tumor cells due to their resistance to radiation. Moreover, RT also induces programmed death ligand 1 (PD-L1) upregulation on tumor cells, which has an inhibitory effect on T lymphocytes. Therefore, therapy based on CIC must selectively target the restricted steps of antitumor immunity. Herein, the authors design a versatile three-in-one assembling nanoparticle that can simultaneously execute these obstacles. The amphiphilic peptide drug conjugate NIA-D1, containing the hydrophobic radio-sensitizer 2-(2-nitroimidazol-1-yl) acetic acid (NIA), a peptide substrate of matrix metalloproteinase-2, and a hydrophilic PD-L1 antagonist D PPA-1, is constructed and co-assembled with hydrophobic Toll-like receptor (TLR) 7/8 agonist R848 to form nanoparticle NIA-D1@R848. The NIA-D1@R848 nanoparticles combined with RT can trigger the apoptosis of tumor cells and initiate the CIC. In the presence of R848, it promotes the maturation of dendritic cells, which together with protein programmed cell death protein 1 (PD-1) and its ligand PD-L1  blockade to relieve T cell suppression, and amplify the antitumor immune cycle. In conclusion, a functionalized three-in-one nanoparticle NIA-D1@R848 is successfully constructed, which can induce strong systemic antitumor immune response.

• Authors: Xueqin Zhu, Xiaoxi Wang, Bingyu Li, Yun Zhang, Yalan Chen, Wenyan Zhang, Yan Wang, Wenjie Zhai, Zimai Liu, Sijia Liu, Jiaxin Sun, Zhenzhen Chen, Yanfeng Gao
• Journal: Small (Weinheim an der Bergstrasse, Germany) (Small) Vol. 18 Issue 20 Pg. e2107001 (05 2022) ISSN: 1613-6829 [Electronic] Germany
• PMID: 35434938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Wiley-VCH GmbH.

Chemical References

• Adjuvants, Immunologic
• B7-H1 Antigen
• Peptides
• TLR7 protein, human
• Toll-Like Receptor 7
• Toll-Like Receptor 8
• Matrix Metalloproteinase 2

Topics

• Adjuvants, Immunologic
• B7-H1 Antigen (metabolism)
• Cell Line, Tumor
• Humans
• Immunity
• Immunotherapy
• Matrix Metalloproteinase 2
• Nanoparticles (chemistry)
• Neoplasms (drug therapy)
• Peptides (therapeutic use)
• Toll-Like Receptor 7
• Toll-Like Receptor 8 (agonists)