2. Academic Validation
  3. NQO1-responsive Trimethyl lock benzoquinone: A cleavable linker strategy for antibody-drug conjugates

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

  • J Control Release. 2025 Dec 11:390:114534. doi: 10.1016/j.jconrel.2025.114534.
Zihao Wang 1,  Kai Liu 2,  Chao Shang 3,  Xiangyu Yan 4,  Yuchao Dong 1,  Dapeng Li 5,  Yiquan Li 3,  Cuiling Zhang 3,  Wei Ren 1,  Chengyuan Ma 5,  Huan Wang 6,  Xiao Li 7,  Shiyong Fan 8,  Wu Zhong 9
Affiliations

Affiliations

  • 1 National Engineering Research Center for the Emergency Drug, Beijing 100039, China.
  • 2 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130122, China; Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130000, China.
  • 3 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130122, China.
  • 4 State Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan 410083, China.
  • 5 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130000, China.
  • 6 State Key Laboratory of Rare Earth Resource Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China. Electronic address: [email protected].
  • 7 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130122, China. Electronic address: [email protected].
  • 8 National Engineering Research Center for the Emergency Drug, Beijing 100039, China. Electronic address: [email protected].
  • 9 National Engineering Research Center for the Emergency Drug, Beijing 100039, China. Electronic address: [email protected].
PMID: 41389965 DOI: 10.1016/j.jconrel.2025.114534
Abstract

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.

Keywords

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

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