掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s42004-026-02019-1

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出版者・発行元：openRxiv  

Current precision oncology—molecular targeted therapies and immunotherapies—relies on genomic or expressed biomarkers, yet most cancer patients remain ineligible for these treatments. Here, we establish enzyme activity as an actionable and orthogonal axis for precision cancer medicine. Strategic activity-based screening of mouse organs and human clinical specimens with a panel of enzyme-reactive fluorescence probes identified β-galactosidase 1 (GLB1) and β-hexosaminidases (HEX) as broadly elevated tumor-selective biomarkers. Leveraging these activities, we developed 7-ethyl-10-hydroxycamptothecin (SN38)-based GLB1- and HEX-reactive prodrugs. These prodrugs exhibited dramatically reduced systemic toxicities and improved therapeutic windows, compared to a clinically used SN38-based prodrug, irinotecan (CPT-11). Both prodrugs demonstrated activity-dependent therapeutic efficacy, affording a dramatic reduction of tumor volumes across multiple in vivo models, including a subcutaneous patient-derived xenograft (PDX) of lung squamous cell carcinoma that lacked genetic alterations targeted by current precision medicine. Furthermore, this strategy is broadly applicable across various cytotoxic payloads, establishing a generalizable platform for small-molecule precision medicines. Our results define an enzyme-targeting paradigm for precision oncology, in which fluorescence probes serve as companion diagnostic tools to guide development and selection of appropriately targeted prodrugs, which are expected to provide safer and more efficacious treatment options for cancer patients with elevated enzyme activities.

DOI： 10.64898/2026.04.14.717586

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Visualizing specific enzyme activities in living systems is important in biomedical research, and Raman imaging probes are particularly suitable for simultaneous multiplexed detection of plural enzyme activities due to their narrow signal peak widths. Here, we present a molecular design strategy for enzyme-activity-detecting Raman probes based on control of aggregation. The probe itself is soluble and diffusive in aqueous solution due to its hydrophilic substrate moiety, but hydrolysis by the target enzyme affords a hydrophobic product that forms aggregates, thereby increasing the local dye concentration, which in turn results in a stronger Raman signal that enables visualization of the enzyme activity. We validated the molecular design by developing Raman probes targeting aminopeptidase, glycosidase and carboxypeptidase. The vibrational frequency can be shifted by isotope-editing, and the developed probes were successfully applied to visualize the activities of aminopeptidase and glycosidase in live cultured cells and spheroids.

DOI： 10.1021/acs.analchem.5c02231

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Coumarin-hemicyanine (CHC) hybrid fluorophores bearing an intramolecular nucleophile have been reported as ratiometric fluorescent probes based on the equilibrium between the π-conjugated open and cyclic closed forms. Here, we report red-shifted CHC derivatives that can serve as scaffold dyes of activated fluorescent probes and activated Raman probes. We prepared a series of cyano-substituted CHC derivatives and found that substitution at C-4 of the coumarin moiety is effective in extending the absorption wavelength. The near-infrared (NIR) emission of these 4CN-CHC derivatives exhibits high tissue penetration. Dual-color imaging with 4CN-CHC enabled ratiometric monitoring of the lysosomal pH changes. Furthermore, the coherent anti-Stokes Raman scattering (CARS) signals of 4CN-CHC derivatives could be regulated by modifying the open/closed equilibrium, and the different patterns of CARS spectra enabled us to perform multicomponent imaging. Thus, these 4CN-CHC derivatives expand the repertoire of functional probes for NIR and multiplexed vibrational imaging.

DOI： 10.1021/acs.analchem.5c02714

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Chemical Society (ACS)  

DOI： 10.1021/jacs.5c04193

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