An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity
Hypoxia (i.e., pO2 ≤ ~1.5 %) is an important characteristic of tumor microenvironments that directly correlates with resistance against first-line therapies and tumor proliferation/infiltration. The ability to accurately identify hypoxic tumor cells/tissue could afford tailored therapeutic regimens for personalized treatment, the development of more-effective therapies, and discerning the mechanisms underlying disease progression. Fluorogenic constructs currently developed for identifying such tumor cells/tissue operate by targeting the bioreductive activity of primarily the nitroreductase (NTR) class of enzymes, but collectively such constructs unfortunately present photophysical and/or physicochemical shortcomings that could limit their effectiveness upon implementation. To overcome these limitations, we present the rational design, development, and evaluation of the first activatable ultracompact xanthene core-based molecular probe (NO2-Rosol) for selectively imaging NTR activity that affords an “OFF-ON” near-infrared (NIR) fluorescence response (ca. > 700 nm) alongside a remarkable Stokes shift (ca. > 150 nm) via NTR activity-facilitated modulation to its energetics whereby the resultant interplay discontinues an intramolecular d-PET fluorescence-quenching mechanism transpiring between directly-linked electronically-uncoupled π-systems comprising its components. DFT calculations guided selection of a suitable fluorogenic scaffold and nitroaromatic moiety candidate that when adjoined could (i) afford such photophysical response upon bioreduction by upregulated NTR activity in hypoxic tumor cells/tissue and (ii) employ a retention mechanism strategy that capitalizes on an inherent physical property of the NIR fluorogenic scaffold for achieving signal amplification. NO2-Rosol demonstrated 705 nm NIR fluorescence emission and a 157 nm Stokes shift, selectivity for NTR over relevant bioanalytes, and a 28- and 12-fold fluorescence enhancement in solution and between cells cultured under different oxic conditions, respectively. Finally, in establishing feasibility for NO2-Rosol to provide favorable contrast levels in in solutioand in vitrostudies, we anticipate NO2-Rosol similarly doing so in future studies towards its translation.
- Research Organization:
- Stanford Univ., CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- Grant/Contract Number:
- SC0008397; R21 CA205564-01A1; T32 CA118681
- OSTI ID:
- 1801819
- Alternate ID(s):
- OSTI ID: 1582473
- Journal Information:
- Sensors and Actuators. B, Chemical, Vol. 306, Issue C; ISSN 0925-4005
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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