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用于癌症治疗的条件性可激活细胞焦亡诱导剂

Conditionally Activatable Pyroptosis-Inducing Agents for Cancer Therapy.

作者信息

Zhang Yongkang, Wang Yaming, Zhang Hao, Qi Fan, Li Eryan, Li Changhua

机构信息

State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Key Laboratory of Functional Polymer Materials of Ministry of Education College of Chemistry Nankai University Tianjin 300071 China.

出版信息

Small Sci. 2023 Dec 15;4(2):2300135. doi: 10.1002/smsc.202300135. eCollection 2024 Feb.

DOI:10.1002/smsc.202300135
PMID:40212358
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11935172/
Abstract

Pyroptosis is a recently defined form of immunogenic cell death that shows great promise in cancer immunotherapy. However, almost all small-molecule pyroptosis-inducing agents (PyAs) reported to date indiscriminately induce pyroptosis in multiple cell types, leading to off-target pyroptotic death of normal and immune cells. One promising approach to addressing this biosafety issue is the design of conditionally activatable PyAs that specifically respond to disease biomarkers. Herein, a general solution for facilely tailoring and synthesizing activatable PyAs based on a newly developed class of photoactive PyAs, termed PyPSs, is reported. The unique structurally encoded properties of PyPSs, including endo reticulum targeting, hypoxia tolerance, and sensing properties, excitingly meet a demanding set of performance requirements for constructing conditionally activatable PyAs for cancer immunotherapy. Based on PyPS-1 scaffold, hypoxia-activatable PyPS-NF as a proof-of-concept example is prepared, demonstrating specific hypoxia-activated pyroptotic cell death and favorable immunotherapeutic efficacy of solid tumors. Herein, a general design strategy for tailoring activatable PyAs to precisely control GSDME-mediated cell pyroptosis is established, with great potential to advance cancer immunotherapy.

摘要

细胞焦亡是一种最近定义的免疫原性细胞死亡形式，在癌症免疫治疗中显示出巨大的潜力。然而，迄今为止报道的几乎所有小分子细胞焦亡诱导剂（PyAs）都会在多种细胞类型中无差别地诱导细胞焦亡，导致正常细胞和免疫细胞发生脱靶性细胞焦亡死亡。解决这一生物安全问题的一种有前景的方法是设计对疾病生物标志物有特异性反应的条件可激活PyAs。在此，报道了一种基于新开发的一类光活性PyAs（称为PyPSs）来简便定制和合成可激活PyAs的通用解决方案。PyPSs独特的结构编码特性，包括内质网靶向性、低氧耐受性和传感特性，令人兴奋地满足了构建用于癌症免疫治疗的条件可激活PyAs所需的一系列严格性能要求。基于PyPS - 1支架，制备了低氧可激活的PyPS - NF作为概念验证示例，证明了其对实体瘤具有特异性低氧激活的细胞焦亡死亡和良好的免疫治疗效果。在此，建立了一种定制可激活PyAs以精确控制GSDME介导的细胞焦亡的通用设计策略，具有推进癌症免疫治疗的巨大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72d2/11935172/2936513384c1/SMSC-4-2300135-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72d2/11935172/2936513384c1/SMSC-4-2300135-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72d2/11935172/cc110843c170/SMSC-4-2300135-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72d2/11935172/53d53194f8b1/SMSC-4-2300135-g001.jpg
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本文引用的文献

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A Highly Water-Soluble Aggregation-Induced Emission Luminogen with Anion-π Interactions for Targeted NIR Imaging of Cancer Cells and Type I Photodynamic Therapy.一种具有阴离子-π 相互作用的高水溶性聚集诱导发射发光体，用于癌细胞的靶向近红外成像和 I 型光动力疗法。
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