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Nano Research 2022, 15(4): 3398-3408 https://doi.org/10.1007/s12274-021-3946-2
Research Article | Issue | Published: 15 December 2021

Inspired heat shock protein alleviating prodrug enforces immunogenic photodynamic therapy by eliciting pyroptosis

Show Author's Information Junjie Zhou1,§,  Xianbin Ma2,§,  Hao Li1,  Derun Chen1,  Liang Mao1,  Leilei Yang1,  Tian Zhang2,  Wei Qiu2,  Zhigang Xu2( ),  Zhi-Jun Sun1 ( )
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, China

§ Junjie Zhou and Xianbin Ma contributed equally to this work.

Keywords:
immunotherapy, photodynamic therapy, tumor microenvironment, heat shock proteins, pyroptosis
Topics:
Drug delivery
Cite this article:
Zhou J, Ma X, Li H, et al. Inspired heat shock protein alleviating prodrug enforces immunogenic photodynamic therapy by eliciting pyroptosis. Nano Research, 2022, 15(4): 3398-3408. https://doi.org/10.1007/s12274-021-3946-2
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Abstract Full text Electronic supplementary material About this article

Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.


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Electronic supplementary material
About this article

Inspired heat shock protein alleviating prodrug enforces immunogenic photodynamic therapy by eliciting pyroptosis

Show Author's information Junjie Zhou1,§, Xianbin Ma2,§, Hao Li1, Derun Chen1, Liang Mao1, Leilei Yang1, Tian Zhang2, Wei Qiu2, Zhigang Xu2( ), Zhi-Jun Sun1 ( )
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, China

§ Junjie Zhou and Xianbin Ma contributed equally to this work.

Abstract

Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.

Keywords: immunotherapy, photodynamic therapy, tumor microenvironment, heat shock proteins, pyroptosis

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Publication history
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Acknowledgements

Publication history

Received: 08 August 2021
Revised: 18 October 2021
Accepted: 24 October 2021
Published: 15 December 2021
Issue date: April 2022

Copyright

©  Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021

Acknowledgements

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Nos. 82072996 (Z.-J. S.), 81874131 (Z.-J. S.), and 51703187 (Z. X.)), National Key Research and Development Program (No. 2017YFSF090107), the Chongqing Talent Plan for Young TopNotch Talents (No. CQYC202005029 (Z. X.)), the Hubei Province Natural Science Funds for Distinguished Young Scholar (No. 2017CFA062 (Z.-J. S.)), and Innovative Research Team of High-level Local Universities in Shanghai (No. ZLCX20180500 (Z.-J. S.)).

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