Li Keliang, Sun Yuhang, Ma Zonglin, Chen Yuping, Li Xinglin, Dong Guoqiang, Liu Dan, Sheng Chunquan, Wu Shanchao
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2025 Jun 26;68(12):12402-12413. doi: 10.1021/acs.jmedchem.4c02822. Epub 2025 Apr 2.
Hypoxia is a state of low oxygen tension that is found in numerous solid tumors. Generally, nitroreductase (NTR) is overexpressed and directly correlated with the hypoxic status in solid tumors, supporting the hypothesis that prodrug could be activated by intracellular NTR and lead to potential antitumor therapy. Herein, evodiamine-based hypoxia-targeting theranostic agents were developed to enhance the antitumor efficacy. These agents are activated by NTR-mediated -nitrobenzyl reduction, enabling simultaneous fluorophore activation for imaging and therapeutic agent (3-fluoro-10-hydroxyl-evodiamine) release for solid tumor treatment. After a systemic test, these theranostic agents were verified to be selectively activated by NTR with excellent fluorescence properties and antitumor potency. In particular, exhibited excellent antitumor activity (tumor growth inhibition value (TGI) = 76.1%) in HCT116 xenograft nude mice with favorable tumor-targeted properties and low toxicity. Thus, this NTR-responsive theranostic agent provides a platform for constructing prodrugs to release monitoring and active substances controlled by the hypoxic status.
缺氧是一种在多种实体瘤中存在的低氧张力状态。一般来说，硝基还原酶（NTR）在实体瘤中过表达，且与缺氧状态直接相关，这支持了前药可被细胞内NTR激活并导致潜在抗肿瘤治疗的假说。在此，开发了基于吴茱萸碱的缺氧靶向诊疗试剂以提高抗肿瘤疗效。这些试剂通过NTR介导的对硝基苄基还原而被激活，能够同时激活荧光团用于成像，并释放治疗剂（3-氟-10-羟基吴茱萸碱）用于实体瘤治疗。经过全身测试，这些诊疗试剂被证实可被NTR选择性激活，具有优异的荧光特性和抗肿瘤效力。特别是，在HCT116异种移植裸鼠中表现出优异的抗肿瘤活性（肿瘤生长抑制值（TGI）=76.1%），具有良好的肿瘤靶向特性和低毒性。因此，这种NTR响应性诊疗试剂为构建受缺氧状态控制的前药释放监测和活性物质提供了一个平台。
