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  • A number of chemical strategies have been developed to


    A number of chemical strategies have been developed to design activatable optical imaging probes and have been summarized in several excellent reviews 11., 12., 13., 14., 15.. Fluorogenic enzyme substrates are one of the most explored activatable probe types for enzyme detection. These probes contain a fluorophore that is capped with an enzyme recognition substrate to quench their fluorescence, and after enzymatic removal of the capping substrate, the fluorescence is recovered. Extremely high turn on ratios are commonly observed for these probes 16., 17.. Pre-quenched probes are another type of widely used activatable optical imaging probes, in which a fluorophore and a quencher are linked together via an enzyme-cleavable peptide substrate. The initial fluorescence of the fluorophore is quenched due to Förster resonance energy transfer (FRET), and upon cleavage by a specific enzyme, the quencher is released to eliminate the FRET quenching effect, resulting in strong fluorescence recovery 8., 18.. Pre-quenched probes with other quenching mechanisms involving fluorophore H-dimer formation [19] and photon-induced NS 11394 transfer (PeT) have also been reported. Pre-quenched probes have found successful applications for in vivo imaging of various enzymes, such as cathepsins [20], MMPs [21], caspases [22], and β-lactamase [23]. Enzyme-triggered self-assembly of small molecules into nanostructures has recently been exploited as a novel approach to build activatable probes for molecular imaging 24., 25.. The approach initially uses small molecules, which upon interaction with a target enzyme, form small probes that are converted into nanostructures through self-assembly. The probes are trapped and accumulated at the target site, producing a strong fluorescence signal. In a pioneering work, Rao and co-workers [26] employed a first-order bioorthogonal cyclization reaction between a D-cysteine residue and a 2-cyano-6-hydroxyquinoline (CHQ) moiety to construct a caspase-3/7 sensitive self-assembling fluorescent probe (C-SNAF) to image caspase-3/7 activity in living animals [27] (Fig. 2). Caspase-3/7 has been recognized as an “executioner” for cell apoptosis, and imaging its activity can provide invaluable predictive information regarding therapeutic efficacy and anti-cancer drug screening. C-SNAF is designed to have (1) D-cysteine and CHQ moieties linked to an amino luciferin scaffold, (2) a DEVD capping sequence with an ethyl disulfide, and (3) an NIR fluorophore Cy5.5 that is amenable to in vivo imaging (Fig. 2a). Compared to saline treatment, significantly brighter images were obtained in response to chemotherapy for C-SNAF in nude mice bearing subcutaneous HeLa tumors that received three rounds of doxorubicin (DOX) through i.v. administration (Fig. 2b). The brighter images were associated with caspase-3/7 activity in the tumors undergoing chemotherapy. Importantly, the degree of tumor size decrease during the course of chemotherapy directly correlated with the intensity of fluorescence in the tumors enhanced by C-SNAF, suggesting the potential of C-SNAF for early monitoring of tumor therapeutic efficacy (Fig. 2c). Moreover, fluorescence quenching/dequenching was also integrated with the self-assembly approach to construct pre-quenched probes, which could not only turn on fluorescence upon caspase-3/7 recognition but also show enhanced retention in apoptotic tumor cells. The self-assembly approach has also been extended to design a 18F-labeled positron emission tomography (PET) tracer 28., 29. and a Gd-based MRI contrast agent 30., 31., 32. for caspase-3/7, enabling in vivo imaging of tumor cell apoptosis with high sensitivity and high spatial resolution.
    Activatable MRI probes MRI is commonly used in clinics around the world and has the advantages of outstanding tissue-penetration depth and extremely high spatial resolution for in vivo imaging [33]. MRI has relatively poor sensitivity and usually requires contrast agents to enhance the imaging contrast by reducing the local T1 and T2 relaxation times of water protons in pathological tissues. However, most of the current clinical contrast agents are nonspecific and are not capable of imaging biochemical activity; therefore, recent efforts have been devoted to the design of activatable probes for molecular MRI 34., 35., 36., 37.. These activatable probes, whose MR properties (relaxivity) are modulated by a specific molecular target from either receptor binding or molecular activation, are particularly attractive because the resulting signal amplification can greatly improve the detection sensitivity and specificity.