An APN‐Activated Chemiluminescent Probe for Image‐Guided Surgery of Malignant Tumors

Abstract

past few decades. [5] In particular, activatable probes that can be specifically turned on to emit fluorescence by various cancerous biomarkers have been developed, [6] leading to significant improvement in the precision of tumor resection. [7] For instance, Urano et al. have developed a γ-glutamyltranspeptidase-responsive fluorescent probe that can light up tiny ovarian cancer nodules within 10 min [5c] and Bogyo et al. have reported a dual proteasesactivated fluorescent probe with improved specificity and sensitivity in localizing lung cancer metastases of <1 mm in diameter. [8] In spite of these encouraging advances, fluorescence imaging always suffers from some inherent limitations including photo bleaching, shallow tissuepenetration-depth, and high background signal arising from the autofluorescence of biological tissues upon light excitation. In this context, developing new strategies for creating luminescent probes with improved specificity and accuracy in discriminating cancerous lesions from normal tissues during the surgery is fundamentally important. [9] Chemiluminescence has been regarded as an alternative choice of constructing sensitive probes for biosensing and imaging. [10] Unlike fluorescence, chemiluminescence utilizes chemical reactions rather than photoexcitation to trigger the luminescence. As a consequence, chemiluminescence imaging can remarkably suppress the interference of autofluorescence to give rise to higher signal-to-noise ratio and better sensitivity for tumor detection in comparison with conventional fluorescence imaging. [11] As an attempt, Ding et al. have reported a chemiluminescent dioxetane-based nanoparticle for image-guided cancer surgery, [12] but it is an "always-on" probe, which has poor specificity and high background compared to activatable probe, and thus is unfavorable for tumor detection during a surgical practice. In recent years, a series of activatable chemiluminescent probes based on Schaap's dioxetanes have been developed for selective detection and imaging of various biomarkers such as cathepsin B, nitroreductase, β-galactosidase, reactive species, granzyme B and aminopeptidases, both in vitro and in vivo. [13] However, existing activatable chemiluminescent probes have not been explored for image-guided tumor surgery.Aminopeptidase N/CD13 (APN), a transmembrane metalloprotease that can preferentially hydrolyze N-terminal alanine from polypeptides, is the most studied cancer-related aminopeptidase. [14] Plentiful studies have demonstrated that APN is Developing smart molecular probes for assisting surgeons to precisely detect cancerous tissues and to completely remove all of them during the surgery is urgently required. Conventional fluorescent probes allow for tumor detection but with limited signal-to-noise ratio. Herein, an aminopeptidase N/ CD13 (APN)-activated chemiluminescent probe (APN-ACLP) is reported for sensitive imaging and precise resection of malignant tumors. The APN-ACLP probe is based on acryl-substituted phenoxy-dioxetane that is coupled with...

1,2‐Dioxetane‐based Chemiluminescence Probes for Tumor Optical Molecular Imaging

“…[117] In the same year, a similar probe, probe 25, was reported for in vivo tumor imaging and surgery guiding (Figure 15a). [118] β-Galactosidase (β-gal) is a lysosomal hydrolase that hydrolyzes lactose glycosidic bonds. Elevated levels of β-gal are associated with primary ovarian cancers, and its activity can cause decomposition of macromolecular proteoglycan, basement membrane, and extracellular matrix barriers, resulting in metastasis and infiltration of cancer cells.…”

A Tandem‐Locked Chemiluminescent Probe for Imaging of Tumor‐Associated Macrophage Polarization

“…[21][22] Without the requirement of real-time light excitation, chemiluminescence (CL) imaging have minimized background noise and thus higher SBR than fluorescence imaging. [23][24][25][26][27] Recently, biomarker-activatable CL probes have been reported for detection of a variety of biomarkers, including enzymes, [28][29][30][31][32][33][34][35] reactive oxygen and nitrogen species, [10,[36][37][38][39][40][41][42][43] and metabolites. [44][45] However, these CL probes typically emit visible light, and only nine of them emit near-infrared region (NIR) light.…”

Near‐Infrared Photodynamic Chemiluminescent Probes for Cancer Therapy and Metastasis Detection

“…As compared to many other chemiluminophore scaffolds, adamantyliene-1,2dioxetane affords an easier structural modification, which has enabled the development of a series of activatable chemiluminescent probes with turn-on signals, facilitating the detection of biomarkers including RONS (O 2 *À , ONOO À , HNO, 1 O 2 , HClO and H 2 O 2 ), [31][32][33][34][35][36][37][38][39][40][41] small molecules (formaldehyde and H 2 S), [42,43] and enzymes (APN: aminopeptidase N, β-Gal, GGT and NTR). [44][45][46][47][48] Most of them emit visible light, and only six chemiluminophores have been reported to emit near-infrared (NIR) light (emission � 700 nm) (Table S1). However, five of them are unsuitable for in vivo photodynamic therapy (PDT), because they have absorption in the visible range and thus are hard to be excited in tissues.…”