前药
化学
结合
细胞毒性
阿霉素
药理学
免疫疗法
癌症免疫疗法
癌症研究
免疫原性细胞死亡
免疫系统
化疗
免疫学
生物化学
医学
体外
内科学
数学分析
数学
作者
Zhennan Zhao,Xinyu Wang,Jinhui Wang,Yiyi Li,Wenkai Lin,Kai Lu,Jun Chen,Wei Xia,Zong‐Wan Mao
标识
DOI:10.1021/acs.jmedchem.3c00557
摘要
Checkpoint inhibitors have been used with chemotherapy to improve antitumor efficacy. However, overcoming the immunosuppressive effect of chemotherapeutics remains a challenge. We report a nanobody–catalyst conjugate Ru-PD-L1 by fusing a ruthenium catalyst to an anti-PD-L1 nanobody. After administration of Ru-PD-L1 and a doxorubicin (DOX) prodrug, Ru-PD-L1 disrupts the PD-L1/PD-1 interaction and catalyzes the uncaging of the DOX prodrug. The spatially confined release of DOX reduces its systemic toxicity and leads to immunogenic cell death (ICD). The induced ICD triggers antitumor immune responses, which are further amplified by PD-L1 blockade to elicit synergistic chemo-immunotherapy, substantially increasing the number of tumor-infiltrating T-cells by 49.7% compared with the controls, thereby exhibiting high antitumor activity and low cytotoxicity in murine models. The combinational treatment could inhibit the growth of mice tumors by 67.7% compared to the control group. This combinational approach circumvents the negative immunogenic effects of chemotherapeutics and provides a potential chemo-immunotherapy strategy for human cancer treatment.
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