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Nitroreductase-Responsive Bioorthogonal Tetrazine Conjugations in Cancer Cells
Dan Zhang1, Jiaxue Zhang1, Hao Liu1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Abstract:
Prodrugs in response to tumor-overexpressed enzymes offer a targeted approach for cancer therapy. However, this strategy faces several challenges, including poor water solubility, off-target effects, and tumor heterogeneity. To address these limitations, this study developed a novel class of nitroreductase-responsive tetrazine precursors by employing nitrobenzyl as a masking group for dihydrotetrazines (NBdTz), which can be further functionalized with targeting peptides. Furthermore, we have demonstrated a dual tumor-selective on demand bioorthogonal prodrug activation enabled by RGD-NBdTz. RGD promotes tumor cellular uptake by interacting with tumor-associated integrin αvβ3, and subsequent enzymatic reduction of aromatic nitro group of NBdTz by overexpressed Nitroreductase (NTR) among hypoxic tumor microenvironment (TME) leads to the liberation of the bioorthogonal handle tetrazine, resulting in the anticipated bioorthogonal activation of trans-cyclooctene caged payloads through "click-to-release" reactions. We envision the presented NBdTz enabled tumor-selective on demand tetrazine ligation offers new opportunities for cancer therapy.
Insights
This study introduces nitrobenzyl-masked dihydrotetrazines (NBdTz) for targeted cancer therapy. These prodrugs are activated by nitroreductase (NTR) in tumors, releasing tetrazines for bioorthogonal "click-to-release" drug activation.
Area of Science:
- Biochemistry
- Organic Chemistry
- Cancer Therapeutics
Background:
- Prodrugs targeting tumor enzymes offer targeted cancer therapy but face challenges like poor solubility and off-target effects.
- Tumor heterogeneity and the tumor microenvironment (TME) present significant hurdles for effective drug delivery and activation.
Purpose of the Study:
- To develop a novel class of nitroreductase-responsive tetrazine prodrugs (NBdTz) to overcome limitations of current targeted cancer therapies.
- To achieve dual tumor-selective, on-demand bioorthogonal prodrug activation using RGD-functionalized NBdTz.
Main Methods:
- Synthesized nitrobenzyl-masked dihydrotetrazines (NBdTz) and functionalized them with RGD peptides.
- Investigated the tumor-selective activation mechanism involving integrin αvβ3 binding and nitroreductase (NTR) enzymatic activity in hypoxic TME.
- Demonstrated bioorthogonal activation of trans-cyclooctene caged payloads via tetrazine ligation and "click-to-release" reactions.
Main Results:
- Successfully developed RGD-NBdTz prodrugs enabling dual tumor-selective activation.
- Confirmed enhanced cellular uptake via RGD interaction with integrin αvβ3.
- Showcased on-demand release of tetrazine upon NTR-mediated reduction of the nitro group in hypoxic conditions.
- Validated bioorthogonal payload release through click chemistry.
Conclusions:
- The NBdTz platform offers a promising strategy for targeted cancer therapy by enabling on-demand, tumor-specific prodrug activation.
- This approach addresses key challenges in targeted therapy, including solubility and off-target effects.
- The developed system opens new avenues for cancer treatment utilizing bioorthogonal chemistry and targeted prodrug design.
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