A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis
Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tu...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2025
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/182206 |
| _version_ | 1826125082282426368 |
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| author | Wang, Zhimin Lau, Jun Wei Liu, Songhan Ren, Ziheng Gong, Zhiyuan Liu, Xiaogang Xing, Bengang |
| author2 | School of Chemistry, Chemical Engineering and Biotechnology |
| author_facet | School of Chemistry, Chemical Engineering and Biotechnology Wang, Zhimin Lau, Jun Wei Liu, Songhan Ren, Ziheng Gong, Zhiyuan Liu, Xiaogang Xing, Bengang |
| author_sort | Wang, Zhimin |
| collection | NTU |
| description | Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tumor cells (or tissues) and correlate their dynamics with the status of disease in complex living settings for precise theranostics. So far, disparate hypoxia-responsive probe molecules and prodrugs were designed via chemical or enzymatic reactions, yet their capability in real-time reporting pathogenesis development is often compromised due to unrestricted diffusion and less selectivity towards the environmental responsiveness. Herein we present an oxygen-insensitive nitroreductase (NTR)-activatable glycan metabolic reporter (pNB-ManNAz) capable of covalently labeling hypoxic tumor cells and tissues. Under pathophysiological hypoxic environments, the caged non-metabolizable precursor pNB-ManNAz exhibited unique responsiveness to cellular NTR, culminating in structural self-immolation and the resultant ManNAz could incorporate onto cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR-responsive metabolic reporter demonstrated broad applicability for multicellular hypoxia labeling, particularly in the dynamic monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in vivo. We anticipate that this approach holds promise for investigating hypoxia-related pathological progression, offering valuable insights for accurate diagnosis and treatment. |
| first_indexed | 2025-03-09T13:56:29Z |
| format | Journal Article |
| id | ntu-10356/182206 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-03-09T13:56:29Z |
| publishDate | 2025 |
| record_format | dspace |
| spelling | ntu-10356/1822062025-01-14T06:56:01Z A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis Wang, Zhimin Lau, Jun Wei Liu, Songhan Ren, Ziheng Gong, Zhiyuan Liu, Xiaogang Xing, Bengang School of Chemistry, Chemical Engineering and Biotechnology Medicine, Health and Life Sciences Metabolic glycan engineering Nitroreductase-activatable Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tumor cells (or tissues) and correlate their dynamics with the status of disease in complex living settings for precise theranostics. So far, disparate hypoxia-responsive probe molecules and prodrugs were designed via chemical or enzymatic reactions, yet their capability in real-time reporting pathogenesis development is often compromised due to unrestricted diffusion and less selectivity towards the environmental responsiveness. Herein we present an oxygen-insensitive nitroreductase (NTR)-activatable glycan metabolic reporter (pNB-ManNAz) capable of covalently labeling hypoxic tumor cells and tissues. Under pathophysiological hypoxic environments, the caged non-metabolizable precursor pNB-ManNAz exhibited unique responsiveness to cellular NTR, culminating in structural self-immolation and the resultant ManNAz could incorporate onto cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR-responsive metabolic reporter demonstrated broad applicability for multicellular hypoxia labeling, particularly in the dynamic monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in vivo. We anticipate that this approach holds promise for investigating hypoxia-related pathological progression, offering valuable insights for accurate diagnosis and treatment. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) We acknowledge the financial support from National Natural Science Foundation of China (NSFC, 22207010), Beijing Natural Science Foundation (L233031), Young Elite Scientists Sponsorship Program by BAST and Beijing Institute of Technology Research Fund Program for Young Scholars, and MOE Tier 1 RG69/21, RG4/22, RT7/22,A*Star SERC A20E5c0090, awarded at Nanyang Techno-logical University. 2025-01-14T06:56:01Z 2025-01-14T06:56:01Z 2024 Journal Article Wang, Z., Lau, J. W., Liu, S., Ren, Z., Gong, Z., Liu, X. & Xing, B. (2024). A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis. Angewandte Chemie (International Ed. in English), 63(51), e202411636-. https://dx.doi.org/10.1002/anie.202411636 1433-7851 https://hdl.handle.net/10356/182206 10.1002/anie.202411636 39152515 2-s2.0-85206486406 51 63 e202411636 en RG69/21 RG4/22 RT7/22 A20E5c0090 Angewandte Chemie (International ed. in English) © 2024 Wiley-VCH GmbH. All rights reserved. |
| spellingShingle | Medicine, Health and Life Sciences Metabolic glycan engineering Nitroreductase-activatable Wang, Zhimin Lau, Jun Wei Liu, Songhan Ren, Ziheng Gong, Zhiyuan Liu, Xiaogang Xing, Bengang A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title | A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title_full | A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title_fullStr | A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title_full_unstemmed | A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title_short | A nitroreductase-activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| title_sort | nitroreductase activatable metabolic reporter for covalent labeling of pathological hypoxic cells in tumorigenesis |
| topic | Medicine, Health and Life Sciences Metabolic glycan engineering Nitroreductase-activatable |
| url | https://hdl.handle.net/10356/182206 |
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