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Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

Jiayi Ye,  Bo Hou,  Fangmin Chen,  Shunan Zhang,  Muya Xiong,  Tianliang Li,  Yechun Xu,  Zhiai Xu,  Haijun Yu

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Jiayi Ye, Bo Hou, Fangmin Chen, Shunan Zhang, Muya Xiong, Tianliang Li, Yechun Xu, Zhiai Xu, Haijun Yu. Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy[J]. 机械工程学报. doi: 10.1016/j.apsb.2021.09.021
引用本文: Jiayi Ye, Bo Hou, Fangmin Chen, Shunan Zhang, Muya Xiong, Tianliang Li, Yechun Xu, Zhiai Xu, Haijun Yu. Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy[J]. 机械工程学报. doi: 10.1016/j.apsb.2021.09.021
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Jiayi Ye, Bo Hou, Fangmin Chen, Shunan Zhang, Muya Xiong, Tianliang Li, Yechun Xu, Zhiai Xu, Haijun Yu. Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2021.09.021
Citation: Jiayi Ye, Bo Hou, Fangmin Chen, Shunan Zhang, Muya Xiong, Tianliang Li, Yechun Xu, Zhiai Xu, Haijun Yu. Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2021.09.021
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Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

doi: 10.1016/j.apsb.2021.09.021

  • a. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

  • b. University of Chinese Academy of Sciences, Beijing 100049, China;

  • c. School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China;

  • d. CAS Key Laboratory of Receptor Research, and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China;

  • e. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310013, China

基金项目: 

This study was supported by the National Natural Science Foundation of China (51873228, 22074043), International Cooperation Project of Science and Technology Commission of Shanghai Municipality (20430711800, China), the Youth Innovation Promotion Association of CAS (2014218, China), and the Fusion Grant between Fudan University and Shanghai Institute of Materia Medica, CAS (No. FU-SIMM-20182006, China). The Mass Spectrometry System and the cell sorter BD Influx of the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, CAS are gratefully acknowledged. All animal procedures were carried out under the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, CAS.

详细信息
    通讯作者:

    Haijun Yu,E-mail:hjyu@simm.ac.cn

  • 中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383521003634/pdf?md5=cf4757140d21c6e5ebb3dc020f58a3d0&pid=1-s2.0-S2211383521003634-main.pdf

Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

  • a. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

  • b. University of Chinese Academy of Sciences, Beijing 100049, China;

  • c. School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China;

  • d. CAS Key Laboratory of Receptor Research, and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China;

  • e. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310013, China

Funds: 

This study was supported by the National Natural Science Foundation of China (51873228, 22074043), International Cooperation Project of Science and Technology Commission of Shanghai Municipality (20430711800, China), the Youth Innovation Promotion Association of CAS (2014218, China), and the Fusion Grant between Fudan University and Shanghai Institute of Materia Medica, CAS (No. FU-SIMM-20182006, China). The Mass Spectrometry System and the cell sorter BD Influx of the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, CAS are gratefully acknowledged. All animal procedures were carried out under the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, CAS.

    摘要
  • 摘要: Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

     

    Abstract: Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

     

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出版历程
  • 收稿日期:  2021-08-05
  • 修回日期:  2021-08-30
  • 录用日期:  2021-09-07
  • 网络出版日期:  2023-03-17

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