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...
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Veröffentlicht in: | Angewandte Chemie International Edition 2024-12, Vol.63 (51), p.e202411636-n/a |
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Zusammenfassung: | 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.
Under pathophysiological hypoxic environments, the caged non‐metabolizable precursor pNB‐ManNAz exhibited responsiveness to cellular NTR, culminating in structural self‐immolation and the resultant ManNAz could be incorporated onto the cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR‐responsive metabolic reporter demonstrated broad applicability for specific hypoxia labeling in diverse cell lines, particularly in the monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in zebrafish models. |
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ISSN: | 1433-7851 1521-3773 1521-3773 |
DOI: | 10.1002/anie.202411636 |