Journal
CANCER REPORTS
Volume 4, Issue 5, Pages -Publisher
WILEY
DOI: 10.1002/cnr2.1384
Keywords
bioimaging; glioblastoma; hypoxia; NIR fluorescence; smart probe
Categories
Funding
- Department of Energy [DOE DE-SC0008397]
- Ben and Catherine Ivy Foundation
- National Institute of Health [NIH 1S10 OD018130, 2T32CA118681]
- NIH/NCI fellowship [F32 CA213620]
- [T32 CA118681]
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The study introduced a smart probe, NO2-Rosol, for identifying hypoxia by measuring NTR activity in GBM cells, demonstrating its robustness and feasibility for imaging hypoxia at various oxygenation levels.
Background: Tumor hypoxia is a characteristic of paramount importance due to low oxygenation levels in tissue negatively correlating with resistance to traditional therapies. The ability to noninvasively identify such could provide for personalized treatment(s) and enhance survival rates. Accordingly, we recently developed an NIR fluorescent hypoxia-sensitive smart probe (NO2-Rosol) for identifying hypoxia via selectively imaging nitroreductase (NTR) activity, which could correlate to oxygen deprivation levels in cells, thereby serving as a proxy. We demonstrated proof of concept by subjecting a glioblastoma (GBM) cell line to extreme stress by evaluating such under radiobiological hypoxic (pO(2) <= similar to 0.5%) conditions, which is a far cry from representative levels for hypoxia for brain glioma (pO(2) = similar to 1.7%) which fluctuate little from physiological hypoxic (pO(2) = 1.0-3.0%) conditions. Aim: We aimed to evaluate the robustness, suitability, and feasibility of NO2-Rosol for imaging hypoxia in vitro and in vivo via assessing NTR activity in diverse GBM models under relevant oxygenation levels (pO(2) = 2.0%) within physiological hypoxic conditions that mimic oxygenation levels in GBM tumor tissue in the brain. Methods: We evaluated multiple GBM cell lines to determine their relative sensitivity to oxygenation levels via measuring carbonic anhydrase IX (CAIX) levels, which is a surrogate marker for indirectly identifying hypoxia by reporting on oxygen deprivation levels and upregulated NTR activity. We evaluated for hypoxia via measuring NTR activity when employing NO2-Rosol in in vitro and tumor hypoxia imaging studies in vivo. Results: The GBM39 cell line demonstrated the highest CAIX expression under hypoxic conditions representing that of GBM in the brain. NO2-Rosol displayed an 8-fold fluorescence enhancement when evaluated in GBM39 cells (pO(2) = 2.0%), thereby establishing its robustness and suitability for imaging hypoxia under relevant physiological conditions. We demonstrated the feasibility of NO(2-)Rosol to afford tumor hypoxia imaging in vivo via it demonstrating a tumor-to-background of 5 upon (i) diffusion throughout, (ii) bioreductive activation by NTR activity in, and (iii) retention within, GBM39 tumor tissue. Conclusion: We established the robustness, suitability, and feasibility of NO2-Rosol for imaging hypoxia under relevant oxygenation levels in vitro and in vivo via assessing NTR activity in GBM39 models.
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