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Diselenide-Based Dual-Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2022-12-07 , DOI: 10.1002/adhm.202202135 Shu-Cheng Wan 1 , Meng-Jie Ye 2 , Qi-Chao Yang 1 , Tian Zhang 2 , Meng-Jie Zhang 1 , Xian-Bin Ma 2 , Ji-Ming Xu 2 , Shuo Wang 1 , Zhi-Zhong Wu 1 , Lei-Lei Yang 1 , Xue-Meng Shen 1 , Zhigang Xu 2 , Zhi-Jun Sun 1
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2022-12-07 , DOI: 10.1002/adhm.202202135 Shu-Cheng Wan 1 , Meng-Jie Ye 2 , Qi-Chao Yang 1 , Tian Zhang 2 , Meng-Jie Zhang 1 , Xian-Bin Ma 2 , Ji-Ming Xu 2 , Shuo Wang 1 , Zhi-Zhong Wu 1 , Lei-Lei Yang 1 , Xue-Meng Shen 1 , Zhigang Xu 2 , Zhi-Jun Sun 1
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Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor-targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel-oxaliplatin is rationally synthesized, which can be covalently self-assembled with diselenide-containing cross-linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on-target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined αPD-1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long-term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual-responsive diselenide-based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy.
中文翻译：
基于二硒化物的双反应前药作为细胞焦亡诱导剂增强癌症免疫疗法
细胞焦亡被证明可以触发抗肿瘤免疫，并代表了一种有前途的增强癌症免疫治疗的新策略。然而，有效的细胞焦亡诱导剂数量有限且不具有肿瘤靶向能力，这不可避免地会对正常组织造成损害。在此，合理合成了紫杉醇-奥沙利铂的小分子前药，它可以与含二硒化物的交联（Dse11）共价自组装，首次制备二硒化物纳米前药（DSe@POC）诱导细胞焦亡。DSe@POC中的二硒键可以被肿瘤微环境（TME）中的高谷胱甘肽和光动力疗法诱导的活性氧分裂，因此具有优异的TME靶向效应。此外，DSe@POC 能够引发强烈的细胞焦亡以重塑免疫刺激的 TME 并引发强烈的免疫反应。此外，结合α PD-1 疗法通过远隔效应有效抑制远处肿瘤的生长，增强长期免疫记忆反应以排斥再次攻击的肿瘤，并延长生存期。总的来说，DSe@POC 作为第一个基于 TME 双响应二硒化物的细胞焦亡诱导剂，将为癌症免疫治疗开辟一条有吸引力的途径。
更新日期：2022-12-07
中文翻译：
基于二硒化物的双反应前药作为细胞焦亡诱导剂增强癌症免疫疗法
细胞焦亡被证明可以触发抗肿瘤免疫，并代表了一种有前途的增强癌症免疫治疗的新策略。然而，有效的细胞焦亡诱导剂数量有限且不具有肿瘤靶向能力，这不可避免地会对正常组织造成损害。在此，合理合成了紫杉醇-奥沙利铂的小分子前药，它可以与含二硒化物的交联（Dse11）共价自组装，首次制备二硒化物纳米前药（DSe@POC）诱导细胞焦亡。DSe@POC中的二硒键可以被肿瘤微环境（TME）中的高谷胱甘肽和光动力疗法诱导的活性氧分裂，因此具有优异的TME靶向效应。此外，DSe@POC 能够引发强烈的细胞焦亡以重塑免疫刺激的 TME 并引发强烈的免疫反应。此外，结合α PD-1 疗法通过远隔效应有效抑制远处肿瘤的生长，增强长期免疫记忆反应以排斥再次攻击的肿瘤，并延长生存期。总的来说，DSe@POC 作为第一个基于 TME 双响应二硒化物的细胞焦亡诱导剂，将为癌症免疫治疗开辟一条有吸引力的途径。
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