A Photoacoustic Probe for the Imaging of Tumor Apoptosis by Caspase‐Mediated Macrocyclization and Self‐Assembly

Wang, Yuqi; Hu, Xiaoming; Weng, Jianhui; Li, Jinbo; Fan, Quli; Zhang, Yan; Ye, Deju

doi:10.1002/anie.201813748

Cited by 122 publications

(87 citation statements)

References 59 publications

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“…An activatable PET probe was designed for detecting the activity of caspase-3/7 in tumors with amplified signal, which underwent reduction and caspase-triggered intermolecular condensation and self-assembly through the π-π stacking interactions in living subjects (Scheme 1) 21, 30-33. The apoptosis-specific imaging probe [ 18 F] 1 consists of a short caspase substrate Acetyl-Asp-Glu-Val-Asp (DEVD), two pro-active moieties (a side-protected cysteine and CBT) and the raidofluorination group [ 18 F]AmBF 3 on a glycine side chain.…”

Section: Resultsmentioning

confidence: 99%

Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis

Qiu¹,

Wang²,

Li³

et al. 2019

Theranostics

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Purpose: Positron emission tomography (PET) imaging of apoptosis is very important for early evaluation of tumor therapeutic efficacy. A stimuli-responsive probe based on the peptide sequence Asp-Glu-Val-Asp (DEVD), [18F]DEVD-Cys(StBu)-PPG(CBT)-AmBF3 ([18F]1), for PET imaging of tumor apoptosis was designed and prepared. This study aimed to develop a novel smart probe using a convenient radiosynthesis method and to fully examine the sensitivity and specificity of the probe response to the tumor treatment.Methods: The radiolabelling precursor DEVD-Cys(StBu)-PPG(CBT)-AmBF3 (1) was synthesized through multistep reactions. The reduction together with caspase-controlled macrocyclization and self-assembly of 1 was characterized and validated in vitro. After [18F]fluorination in the buffer (pH= 2.5), the radiolabelling yield (RLY), radiochemical purity (RCP) and stability of the probe [18F]1 in PBS and mouse serum were investigated by radio-HPLC. The sensitivity and specificity of [18F]1 for detecting the drug-induced apoptosis was fully evaluated in vitro and in vivo. The effect of cold precursor 1 on the cell uptake and tumor imaging of [18F]1 was also assessed. The level of activated caspase-3 in Hela cells and tumors with or without apoptosis induction was analyzed and compared by western blotting and histological staining.Results: The whole radiosynthesis process of [18F]1 was around 25 min with RLY of 50%, RCP of over 99% and specific activity of 1.45 ± 0.4 Ci/µmol. The probe was very stable in both PBS and mouse serum within 4 h. It can be activated by caspase-3 and then undergo an intermolecular cyclization to form nanosized particles. The retained [18F]1 in DOX-treated HeLa cells was 2.2 folds of that in untreated cells. Within 1 h microPET imaging of the untreated Hela-bearing mice, the injection of [18F]1 resulted in the increase of the uptake ratio of tumor to muscle (T/M) only from 1.74 to 2.18, while in the DOX-treated Hela-bearing mice T/M increased from 1.88 to 10.52 and the co-injection of [18F]1 and 1 even led to the increase of T/M from 3.08 to 14.81.Conclusions: A caspase-responsive smart PET probe [18F]1 was designed and prepared in a kit-like manner. Co-injection of [18F]1 and 1 generated remarkably enhanced tumor uptake and signal-to-noise ratio in the tumor-bearing mice with drug-induced apoptosis, which correlated well with the expression level of activated caspase-3. This early readout of treatment response ensured that the probe [18F]1 could serve as a promising PET imaging probe for timely and noninvasive evaluation of tumor therapy.

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Section: Resultsmentioning

confidence: 99%

Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis

Qiu¹,

Wang²,

Li³

et al. 2019

Theranostics

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Section: Advanced Nir Light For Cell Function Imagingmentioning

confidence: 99%

Advanced Near‐Infrared Light for Monitoring and Modulating the Spatiotemporal Dynamics of Cell Functions in Living Systems

et al. 2020

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Light‐based technique, including optical imaging and photoregulation, has become one of the most important tools for both fundamental research and clinical practice, such as cell signal sensing, cancer diagnosis, tissue engineering, drug delivery, visual regulation, neuromodulation, and disease treatment. In particular, low energy near‐infrared (NIR, 700–1700 nm) light possesses lower phototoxicity and higher tissue penetration depth in living systems as compared with ultraviolet/visible light, making it a promising tool for in vivo applications. Currently, the NIR light‐based imaging and photoregulation strategies have offered a possibility to real‐time sense and/or modulate specific cellular events in deep tissues with subcellular accuracy. Herein, the recent progress with respect to NIR light for monitoring and modulating the spatiotemporal dynamics of cell functions in living systems are summarized. In particular, the applications of NIR light‐based techniques in cancer theranostics, regenerative medicine, and neuroscience research are systematically introduced and discussed. In addition, the challenges and prospects for NIR light‐based cell sensing and regulating techniques are comprehensively discussed.

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“…conjugate AP1‐DEVD‐DOX 6 , in Figure ) have been often administered to tumor‐bearing mice in combination with radiotherapy, which is important to initiate the apoptotic cascade and caspase 3 activation: this combined treatment resulted in a higher extent of apoptotic cells, thus improving the therapeutic outcomes . More recently, the DEVD linker was installed in a caspase 3‐activable photoacoustic probe, which enabled high‐resolution imaging of tumor apoptosis in response to chemotherapy . While caspase 3 has been only recently investigated for drug‐delivery purposes, the functionalization of anticancer agents with peptide substrates of lysosomal endopeptidase legumain has been extensively described in the literature.…”

Section: Exploiting the Hallmarks Of Cancer: Linker Cleavage Promotedmentioning

confidence: 99%

“…[32] More recently,t he DEVD linker was installed in ac aspase 3-activable photoacoustic probe, which enabled high-resolution imaging of tumor apoptosisi nr esponse to chemotherapy. [33] While caspase3has been only recently investigated for drug-delivery purposes, the functionalization of anticancer agents with peptides ubstrates of lysosomal endopeptidase legumain has been extensively described in the literature. However,i nar ecent publication, researchers at Bayer reported the use of legumain-sensitivel inkersf or the design of as o-called antibody-prodrug conjugate (APDC).…”

Section: Carrier + + Drug + + Linkermentioning

confidence: 99%

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

Corso

Pignataro

Belvisi

et al. 2019

Chemistry A European J

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The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well‐known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions).

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A Photoacoustic Probe for the Imaging of Tumor Apoptosis by Caspase‐Mediated Macrocyclization and Self‐Assembly

Cited by 122 publications

References 59 publications

Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis

Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis

Advanced Near‐Infrared Light for Monitoring and Modulating the Spatiotemporal Dynamics of Cell Functions in Living Systems

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

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