Sulfonated Perylene as Three‐in‐One STING Agonist for Cancer Chemo‐Immunotherapy

Activation of stimulator of interferon genes (STING) by cyclic dinucleotides (CDNs) has been considered as a powerful immunotherapy strategy. While promising, the clinical translation of CDNs is still overwhelmed by its limited biostability and the resulting systemic immunotoxicity. Being differenti...

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Published in:Angewandte Chemie International Edition 2024-03, Vol.63 (11), p.e202318799-n/a
Main Authors: Zhao, Xuejie, Zheng, Rijie, Zhang, Bianbian, Zhao, Ying, Xue, Wanli, Fang, Yingfei, Huang, Yongwei, Yin, Meizhen
Format: Article
Language:English
Subjects:
Agonists
Animals
Anticancer properties
Antitumor activity
Biocompatibility
cGAS-STING pathway
chemo-immunotherapy
Immunotherapy
Immunotherapy - methods
Immunotoxicity
Intravenous administration
lung enrichment
Membrane Proteins - genetics
Mice
Neoplasms - drug therapy
Nucleotides, Cyclic
Perylene
Stimulators
STING agonists
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Summary:Activation of stimulator of interferon genes (STING) by cyclic dinucleotides (CDNs) has been considered as a powerful immunotherapy strategy. While promising, the clinical translation of CDNs is still overwhelmed by its limited biostability and the resulting systemic immunotoxicity. Being differentiating from current application of exogenous CDNs to address these challenges, we herein developed one perylene STING agonist PDIC‐NS, which not only promotes the production of endogenous CDNs but also inhibits its hydrolysis. More significantly, PDIC‐NS can well reach lung‐selective enrichment, and thus mitigates the systemic immunotoxicity upon intravenous administration. As a result, PDIC‐NS had realized remarkable in vivo antitumor activity, and backward verified on STING knock out mice. Overall, this study states that PDIC‐NS can function as three‐in‐one small‐molecule STING agonist characterized by promoting the content and biostability of endogenous CDNs as well as possessing good tissue specificity, and hence presents an innovative strategy and platform for tumor chemo‐immunotherapy. This study states that sulfonated perylene can function as three‐in‐one small‐molecular stimulator of interferon genes (STING) agonist that not only promotes the production of endogenous cyclic guanosine monophosphate adenosine monophosphate (cGAMP) but also inhibits its hydrolysis as well as achieves lung‐selective enrichment, and hence presents an innovative platform for tumor chemo‐immunotherapy.
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202318799