Abstract
The Near-infrared Fluorescence (NIRF) molecular imaging of cancer is known to be superior in sensitivity, deeper penetration, and low phototoxicity compared to other imaging modalities. In view of an increased need for efficient and targeted imaging agents, we synthesized a NAD(P)H quinone oxidoreductase 1 (NQO1)-activatable NIR fluorescent probe (NIR-ASM) by conjugating dicyanoisophorone (ASM) fluorophore with the NQO1 substrate quinone propionic acid (QPA). The probe remained non-fluorescent until activation by NQO1, whose expression is largely limited to malignant tissues. With a large Stokes shift (186 nm) and a prominent near-infrared emission (646 nm) in response to NQO1, NIR-ASM was capable of monitoring NQO1 activity in vitro and in vivo with high specificity and selectivity. We successfully employed the NIR-ASM to differentiate cancer cells from normal cells based on NQO1 activity using fluorescence microscopy and flow cytometry. Chemical and genetic approaches involving the use of ES936, a specific inhibitor of NQO1 and siRNA and gene transfection procedures unambiguously demonstrated NQO1 to be the sole target activating the NIR-ASM in cell cultures. NIR-ASM was successfully used to detect and image the endogenous NQO1 in three live tumor-bearing mouse models (A549 lung cancer, Lewis lung carcinoma, and MDMAMB 231 xenografts) with a high signal-to-low noise ratiometric NIR fluorescence response. When the NQO1-proficient A549 tumors and NQO1-deficient MDA-MB-231 tumors were developed in the same animal, only the A549 malignancies activated the NIR-ASM probe with a strong signal. Because of its high sensitivity, rapid activation, tumor selectivity, and nontoxic properties, the NIR-ASM appears to be a promising agent with clinical applications.
Highlights
Biomedical imaging plays an important role in all phases of cancer management including screening, guidance for biopsy excisions, malignancy staging, prognosis and therapy planning, follow-up and in looking for early responses to cancer treatments and to identify patients who are not responding to therapy[1]
Most of the NAD(P)H quinone oxidoreductase 1 (NQO1) activated fluorescent probes were developed based on its property of quinone bio-reduction[20], where the fluorophore-conjugated with the quinone-based NQO1 substrates are held in a quenched non-fluorescent state by a trigger group
Taking these points into consideration and to overcome the limitations of NQ-DCP, we developed a physiologically stable new NQO1 activatable ‘turn-on’ near-infrared fluorescent probe (NIR-ASM) for monitoring endogenous NQO1 activity and noninvasive cancer diagnosis (Fig. 1)
Summary
Biomedical imaging plays an important role in all phases of cancer management including screening, guidance for biopsy excisions, malignancy staging, prognosis and therapy planning, follow-up and in looking for early responses to cancer treatments and to identify patients who are not responding to therapy[1]. The probe NIR-ASM demonstrated high selectivity for NQO1 over the other enzymes/substrates tested, fluorescence resulted from the specific cleavage of QPA by NQO1 in the presence of its co-factor NADH (Fig. 3d).
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