Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug.
Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug.
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DOI：
10.1021/acschembio.1c00933
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发表时间：
2022-03
影响因子：
4
通讯作者：
Zhaoxuan Yang;Xiangjie Luo;Yaying Lin;Jiaqi Huang;Hongyu Lin;Jinhao Gao
中科院分区：
文献类型：
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作者：
Zhaoxuan Yang;Xiangjie Luo;Yaying Lin;Jiaqi Huang;Hongyu Lin;Jinhao Gao
免疫疗法对大多数类型癌症的治疗效果有限，这刺激了人们寻求有效的方法来提高其反应率。在此，我们报告了串联化学免疫治疗级联反应分子前药的设计和合成。这种分子前药首先在弱酸性肿瘤微环境（TME）中释放多柔比星（DOX），以诱导肿瘤细胞的免疫原性细胞死亡（ICD）。在肿瘤细胞凋亡期间释放的半胱天冬酶3/7将NLG 919从前药中释放出来，其抑制吲哚胺2，3-双加氧酶（IDO）的活性并导致TME免疫抑制的缓解。同时，ICD期间释放的肿瘤相关抗原和免疫刺激性细胞因子激活针对肿瘤的免疫应答，导致协同化学免疫治疗。该前药的功效通过体外和体内实验验证，证明了该策略用于癌症治疗的成功。
The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released during tumor cell apoptosis liberates NLG919 from the prodrug, which inhibits the activity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TME immunosuppression. Meanwhile, tumor-associated antigens and immune stimulatory cytokines released during ICD activate the immune response against the tumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug is validated by in vitro and in vivo experiments, demonstrating the success of this strategy for cancer treatment.