数字农科院2.0

NQO1-responsive Trimethyl lock benzoquinone: A cleavable linker strategy for antibody-drug conjugates

文献类型： 外文期刊

作者： Wang, Zihao;Liu, Kai;Shang, Chao;Yan, Xiangyu;Dong, Yuchao;Li, Dapeng;Li, Yiquan;Zhang, Cuiling;Ren, Wei;Ma, Chengyuan;Wang, Huan;Li, Xiao;Fan, Shiyong;Zhong, Wu

作者机构：

关键词： NQO1-responsible linker;Trimethyl lock benzoquinone;Antibody-drug conjugates;Glioma therapy;Drug delivery;Antitumor drug development;Targeted therapy;Cleavable linker

期刊名称： JOURNAL OF CONTROLLED RELEASE

ISSN： 0168-3659

年卷期： 2025 年 390 卷

页码：

收录情况： SCIE（2025版） ; ; EI（2025版）

摘要： Antibody-drug conjugate (ADC) efficacy is hindered by premature systemic payload release and insufficient tumor activation. Here, an NQO1-responsive linker utilizing trimethyl lock benzoquinone is developed to create NRTL-24, a glioma-targeting ADC. In vitro studies showed NRTL-24 maintained plasma stability while achieving NQO1-dependent MMAE release. It demonstrated potent cytotoxicity in EGFR/NQO1-high glioma cells (U251 IC50 = 0.03 nM; T98G IC50 = 0.06 nM), comparable to free MMAE (U251 IC50 = 0.01 nM; T98G IC50 = 0.02 nM). Notably, toxicity dropped significantly in EGFR/NQO1-low normal cells (HMC3 IC50 = 0.58 mM), yielding >10,000 selectivity index. In vivo, NRTL-24 demonstrated superior tumor-targeting ability, significantly prolonging median survival compared to untreated and temozolomide-treated groups while maintaining favorable safety. This NQO1-responsive linker technology enables precise payload activation in tumor while minimizing off-target effects, establishing NRTL-24 as a promising therapeutic candidate. The strategy provides a blueprint for enzyme-targeted ADC development through tumor- selective linker design.

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