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  • br C D May et al

    2019-10-29


    [14] C.D. May, et al., Epithelial-mesenchymal transition and cancer stem cells: a dan-
    O. Bozickovic et al.
    Contents lists available at ScienceDirect
    Biosensors and Bioelectronics
    journal homepage: www.elsevier.com/locate/bios
    A novel triarylboron based ratiometric fluorescent probe for in vivo targeting and specific imaging of cancer 6-NBDG expressing abnormal concentration of GGT 
    T
    a Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College & Department of Chemistry, School of Preclinical Medicine, North Sichuan Medical College, Nanchong, 637000, China
    b Key Laboratory of Photochemistry, Institute of Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100190, China
    c Department of Radiology, Affiliated Hospital of North Sichuan Medical College, China
    Keywords:
    Fluorescence
    Triarylboron
    GGT
    Ovarian cancers
    Targeting 
    Abnormal expression of γ-glutamyltranspeptidase (GGT) in living organisms is closely associated with tumor-igenesis. However, few reported fluorescence probes can specifically respond to abnormal concentration of GGT. Here, by functionalizing triarylboron moiety with three GGT-specific substrate (GSH) units, a novel fluorescence probe, TAB-3-GSH, was developed for detecting GGT. The results showed that TAB-3-GSH selectively responds to abnormally high levels of GGT (100–1000 U/L) rather than to normal GGT levels (< 100 U/L) with ratiometric readout, since the amide linkage can be further hydrolyzed under high GGT levels. TAB-3-GSH was also capable of differentiating GGT-overexpressing ovarian cancer cells from normal cells, because of an improvement in the probe's cell membrane permeability upon reaction with GGT. Moreover, the probe could achieve selective imaging of SKOV-3 tumor site in xenograft mice model. Thus, TAB-3-GSH is a promising probe for tumor tar-geting in vivo.
    1. Introduction
    Cancer is one of the deadliest diseases worldwide, and has become a serious threat to human health(Siegel et al., 2018). One of the main challenges in cancer treatment is the timely and accurate diagnosis of cancer at an early stage, which is very important for the prevention and mitigation of cancer progression(Greenlee et al., 2000). Some tumor-related biomarkers can provide effective diagnosis information and prognosis indications of certain cancers (Blum et al., 2007; Bremer et al., 2001; Wu and Qu, 2015). Typically, γ-glutamyltranspeptidase (GGT), a cell membrane-bound enzyme that selectively catalyzes the cleavage of the γ-glutamyl bond in GSH, is overexpressed in cells of a variety of human cancers, such as cervical and ovarian cancers (Hanigan et al., 1994; Yao et al., 2000). It has been reported that GGT promotes tumor progression, invasion and anticancer-drug resistance, and a high level of GGT in serum is closely related to an increased risk of cancer (Pompella et al., 2006; Hu et al., 2012; Fraser et al., 2007; Ozcan et al., 2012). Therefore, GGT is considered to be a biomarker for
    cancer detection and has been used as a diagnostic and prognostic index of gynecologic cancers in clinical trials (Grimm et al., 2013; Ostapenko et al., 2011; Vandenhaute et al., 2011).
    Fluorescence probes are a promising and powerful tool for tumor-related biomarker imaging because of its high specificity, sensitivity, and non-toxicity in live cells or tissues (Wolfbeis, 2015). Based on the GGT-catalyzed cleavage of γ-glutamyl bond, researchers have success-fully designed and synthesized several fluorescence probes for GGT (Hou et al., 2014; Li et al., 2015; Tong et al., 2016; Wang et al., 2015). Most of them, including our previously reported bioluminescent probe (Berk and Korenblat, 2011), have attempted to achieve higher sensi-tivity and lower detection limits. However, we noticed that the normal GGT level in blood is 5–55 U/L for adult females and 15–85 U/L for adult males, which exceeds the maximum detection concentration of most reported GGT fluorescent probes (Li et al., 2017a). In other words, these probes can be fully reacted to produce maximum fluorescence response for GGT even when they enter the normal body, and thus demonstrate no specificity to cancer patients, whose GGT levels can