An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity

SENSORS AND ACTUATORS B-CHEMICAL

卷:306

Article

Klockow, Jessica L.¹  Hettie, Kenneth S.¹  LaGory, Edward L.²  Moon, Eui Jung²  Giaccia, Amato J.²  Graves, Edward E.^1,2  Chin, Frederick T.¹ 

[1] Dept Radiol, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA

关键词: Hypoxia;    Fluorescence;    Imaging;    Nitroreductase;    Activatable probe;    Near-infrared;   

DOI  :  10.1016/j.snb.2019.127446

来源: Elsevier

【 摘 要 】

Hypoxia (i.e., pO(2) <= similar to 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 Tc-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. 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.

【 授权许可】

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