Abnormal enzymatic activities are directly related to the development of cancers. Identifying the location and expression levels of these enzymes in live cancer cells have considerable importance in ...early-stage cancer diagnoses and monitoring the efficacy of therapies. Small-molecule fluorescent probes have become a powerful tool for the detection and imaging of enzymatic activities in biological systems by virtue of their higher sensitivity, nondestructive fast analysis, and real-time detection abilities. Moreover, due to their structural tailorability, numerous small-molecule enzymatic fluorescent probes have been developed to meet various demands involving real-time tracking and visualizing different enzymes in live cancer cells or
in vivo
. In this review, we provide an overview of recent advances in small-molecule enzymatic fluorescent probes mainly during the past decade, including the design strategies and applications for various enzymes in live cancer cells. We also highlight the challenges and opportunities in this rapidly developing field of small-molecule fluorescent probes for interventional surgical imaging, as well as cancer diagnosis and therapy.
An overview of recent advances in small-molecule enzymatic fluorescent probes for cancer imaging, including design strategies and cancer imaging applications.
Hypoxia, as a characteristic feature of solid tumor, can significantly adversely affect the outcomes of cancer radiotherapy (RT), photodynamic therapy, or chemotherapy. In this study, a strategy is ...developed to overcome tumor hypoxia‐induced radiotherapy tolerance. Specifically, a novel two‐dimensional Pd@Au bimetallic core–shell nanostructure (TPAN) was employed for the sustainable and robust production of O2 in long‐term via the catalysis of endogenous H2O2. Notably, the catalytic activity of TPAN could be enhanced via surface plasmon resonance (SPR) effect triggered by NIR‐II laser irradiation, to enhance the O2 production and thereby relieve tumor hypoxia. Thus, TPAN could enhance radiotherapy outcomes by three aspects: 1) NIR‐II laser triggered SPR enhanced the catalysis of TPAN to produce O2 for relieving tumor hypoxia; 2) high‐Z element effect arising from Au and Pd to capture X‐ray energy within the tumor; and 3) TPAN affording X‐ray, photoacoustic, and NIR‐II laser derived photothermal imaging, for precisely guiding cancer therapy, so as to reduce the side effects from irradiation.
More O2 release: Hypoxia significantly limits the outcome of cancer radiotherapy. TPAN was employed to catalyze the overexpressed endogenous H2O2 for sustainable O2 supplement. Moreover, the catalytic ability could be enhanced by plasmon resonance triggered by NIR‐II laser irradiation, so as to overcome tumor hypoxia and enhance radio sensitization.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species to kill cancer cells. However, a high concentration of glutathione (GSH) is present in cancer ...cells and can consume reactive oxygen species. To address this problem, we report the development of a photosensitizer–MnO2 nanosystem for highly efficient PDT. In our design, MnO2 nanosheets adsorb photosensitizer chlorin e6 (Ce6), protect it from self‐destruction upon light irradiation, and efficiently deliver it into cells. The nanosystem also inhibits extracellular singlet oxygen generation by Ce6, leading to fewer side effects. Once endocytosed, the MnO2 nanosheets are reduced by intracellular GSH. As a result, the nanosystem is disintegrated, simultaneously releasing Ce6 and decreasing the level of GSH for highly efficient PDT. Moreover, fluorescence recovery, accompanied by the dissolution of MnO2 nanosheets, can provide a fluorescence signal for monitoring the efficacy of delivery.
A photosensitizer–MnO2 nanosystem has been designed for highly efficient photodynamic therapy. The nanosystem can react with intracellular glutathione (GSH), decreasing the level of GSH, releasing the photosensitizer completely, and thus improving the therapeutic efficiency.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Organic dye based NIR‐II fluorescent probes, owing to their high signal‐to‐background ratio and deeper penetration, are highly useful for deep‐tissue high‐contrast imaging in vivo. However, it is ...still a challenge to design activatable NIR‐II fluorescent probes. Here, a novel class of polymethine dyes (NIRII‐RTs), with bright (quantum yield up to 2.03 %), stable, and anti‐solvent quenching NIR‐II emission, together with large Stokes shifts, was designed. Significantly, the novel NIR‐II dyes NIRII‐RT3 and NIRII‐RT4, equipped with a carboxylic acid group, can serve as effective NIR‐II platforms for the design of activatable bioimaging probes with high contrast. As a proof of concept, a series of target‐activatable NIRII‐RT probes (NIRII‐RT‐pH, NIRII‐RT‐ATP and NIRII‐RT‐Hg) for pH, adenosine triphosphate (ATP), and metal‐ion detection, were synthesized. By applying the NIRII‐RT probe, the real‐time monitoring of drug‐induced hepatotoxicity was realized.
The presented work reports a new class of polymethine dyes (NIRII‐RTs) with bright, stable, and anti‐quenching NIR‐II emissions together with large Stokes shifts. Importantly, by introducing the carboxylic acid functional group, the novel dyes NIRII‐RT3 and NIRII‐RT4 can serve as effective NIR‐II platforms for the design of activatable bioimaging probes with high contrast.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ferroptosis exhibits potential to damage drug‐resistant cancer cells. However, it is still restricted with the “off‐target” toxicity from the undesirable leakage of metal ions from ferroptosis ...agents, and the lack of reliable imaging for monitoring the ferroptosis process in living systems. Herein, we develop a novel ternary alloy PtWMn nanocube as a Mn reservoir, and further design a microenvironment‐triggered nanoplatform that can accurately release Mn ions within the tumor to increase reactive oxygen species (ROS) generation, produce O2 and consume excess glutathione for synergistically enhancing nonferrous ferroptosis. Moreover, this nanoplatform exerts a responsive signal in high‐field magnetic resonance imaging (MRI), which enables the real‐time report of Mn release and the monitoring of ferroptosis initiation through the signal changes of T1‐/T2‐MRI. Thus, our nanoplatform provides a novel strategy to store, deliver and precisely release Mn ions for MRI‐guided high‐specificity ferroptosis therapy.
A novel ternary alloy PtWMn nanoplatform is developed as a Mn reservoir that exhibits efficient storage, specific delivery and accurate release of Mn ions for high‐specificity ferroptosis‐based cancer therapy. Such a smart nanoplatform can exert a responsive imaging signal in dual‐mode (T1‐ or T2‐weighted) high‐field MRI, which enables the real‐time monitoring of Mn release within the tumor microenvironment and of ferroptosis initiation.
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Small‐molecule‐based second near‐infrared (NIR‐II) activatable fluorescent probes can potentially provide a high target‐to‐background ratio and deep tissue penetration. However, most of the reported ...NIR‐II activatable small‐molecule probes exhibit poor versatility owing to the lack of a general and stable optically tunable group. In this study, we designed NIRII‐HDs, a novel dye scaffold optimized for NIR‐II probe development. In particular, dye NIRII‐HD5 showed the best optical properties such as proper pKa value, excellent stability, and high NIR‐II brightness, which can be beneficial for in vivo imaging with high contrast. To demonstrate the applicability of the NIRII‐HD5 dye, we designed three target‐activatable NIR‐II probes for ROS, thiols, and enzymes. Using these novel probes, we not only realized reliable NIR‐II imaging of different diseases in mouse models but also evaluated the redox potential of liver tissue during a liver injury in vivo with high fidelity.
A series of O‐HD‐like dyes (NIRII‐HDs) with bright and stable NIR‐II emission together with proper pKa is reported. By decorating the tunable hydroxyl group, the novel NIR‐II dye NIRII‐HD5 can serve as an effective platform to design various activatable NIR‐II probes for reliable in vivo bioimaging with high contrast.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). ...Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe2O4@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe2O4) as the nanoenzyme. The synthetic MnFe2O4@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H2O2 to produce O2 to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe2O4@MOF is able to persistently consume GSH in the presence of H2O2, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.
A hydrogen peroxide (H2O2)‐responsive MnFe2O4@MOF nanostructure with continuous auto‐generating oxygen and meanwhile decreasing glutathione capacity in the tumor microenvironment (TME) is developed for enhancing the photodynamic therapy antitumor therapeutic effect. This multifunctional nanoplatform integrating treatment and imaging, along with continuous modulation of TME, could promote more precise and effective treatment in future clinical applications.
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Nanozymes with intrinsic enzyme‐like characteristics have attracted enormous research interest in biological application. However, there is a lack of facile approach for evaluating the catalytic ...activity of nanozymes in living system. Herein, we develop a novel manganese‐semiconducting polymer‐based nanozyme (MSPN) with oxidase‐like activity for reporting the catalytic activity of itself in acid‐induced cancer therapy via ratiometric near‐infrared fluorescence (NIRF)‐photoacoustic (PA) molecular imaging. Notably, MSPN possess oxidase‐like activity in tumor microenvironment, owing to the mixed‐valent MnOx nanoparticles, which can effectively kill cancer cells. Because the semiconducting polymer (PFODBT) is conjugated with oxidase‐responsive molecule (ORM), the catalytic activity of nanozyme can be correlated with the ratiometric signals of NIRF (FL695/FL825) and PA (PA680/PA780), which may provide new ideas for predicting anticancer efficacy of nanozymes in living system.
A manganese‐semiconducting polymer‐based nanozyme (MSPN) is developed for real‐time reporting the catalytic activity of itself in acid‐activated cancer therapy by ratiometric near‐infrared fluorescence (NIRF)‐photoacoustic (PA) molecular imaging. The nanoplatform can self‐monitor the activation of nanozymes during cancer therapy, which has potential to predict therapeutic effects in vivo and guide nanoenzymes in personalized cancer treatment.
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Acute hepatitis is a major problem affecting public health and has attracted more and more attention. Generally, as the standard means, blood tests are taken for evaluating hepatitis. However, such ...tests fail to accurately reflect the level of hepatitis in vivo. Herein, two highly selective ratiometric fluorescent probes are designed to track peroxynitrite (ONOO−) as the hepatitis indicator, and further evaluate acute liver injury in vivo through dye‐grafted upconversion nanoparticles (UCNPs). Specifically, upconversion luminescence of nanoprobes at 540 or 660 nm can be quenched by the designed and synthesized chromophore E‐CC or H‐CC, that can be destroyed by ONOO− via energy transfer (ET) process, while the upconversion luminescence intensity at 810 nm remains the same. Thus, the developed nanoprobes can be used for ratiometric detection (I540/I660 or I660/I810) of ONOO−. Moreover, the developed near infrared ratiometric nanoprobes can highly selectively detect ONOO−, which can eliminate the interference of HOCl and SO32−. Finally, it is demonstrated that this highly selective ratiometric nanosystem can achieve effective detection of ONOO− in living cells and CCl4‐induced acute liver injury models. It provides some reference value for clinical detection of hepatotoxicity.
Highly selective near‐infrared ratiometric fluorescent nanoprobes are designed to track the acute hepatotoxicity‐related reactive nitrogen species (RNS) peroxynitrite ONOO−. The nanosystem can estimate the content of ONOO− based on relative fluorescence intensity, and to further realize the assessment of acute liver injury in vivo.
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The combination of nanostructures with biomolecules leading to the generation of functional nanosystems holds great promise for biotechnological and biomedical applications. As a naturally occurring ...biomacromolecule, DNA exhibits excellent biocompatibility and programmability. Also, scalable synthesis can be readily realized through automated instruments. Such unique properties, together with Watson-Crick base-pairing interactions, make DNA a particularly promising candidate to be used as a building block material for a wide variety of nanostructures. In the past few decades, various DNA nanostructures have been developed, including one-, two- and three-dimensional nanomaterials. Aptamers are single-stranded DNA or RNA molecules selected by Systematic Evolution of Ligands by Exponential Enrichment (SELEX), with specific recognition abilities to their targets. Therefore, integrating aptamers into DNA nanostructures results in powerful tools for biosensing and bioimaging applications. Furthermore, owing to their high loading capability, aptamer-modified DNA nanostructures have also been altered to play the role of drug nanocarriers for
in vivo
applications and targeted cancer therapy. In this review, we summarize recent progress in the design of aptamers and related DNA molecule-integrated DNA nanostructures as well as their applications in biosensing, bioimaging and cancer therapy. To begin with, we first introduce the SELEX technology. Subsequently, the methodologies for the preparation of aptamer-integrated DNA nanostructures are presented. Then, we highlight their applications in biosensing and bioimaging for various targets, as well as targeted cancer therapy applications. Finally, we discuss several challenges and further opportunities in this emerging field.
We survey advances in biosensing, bioimaging and cancer therapy applications of aptamer-integrated DNA nanostructures in this review.
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