Abstract

Companion diagnostics (CDx) have emerged as valuable tools for monitoring biomarkers essential for drug activation and therapeutic response, enabling personalized treatment strategies. However, the current FDA-approved CDx is limited to in vitro testing, making it challenging to assess the real-time drug efficacy. Moreover, evaluation of treatment responses solely based on drug release or activation may disregard tumor heterogeneity. To address these challenges, we have developed a cascade-responsive small molecule Cbl-DEVD-Hcy for simultaneous cancer therapy and the timely evaluation of therapy effectiveness in vivo. Upon cleavage by tumor-cell-overexpressed carboxylesterase, chlorambucil (Cbl) can be released to induce tumor cell apoptosis and activate caspase-3. This activation triggers the production of the near-infrared dye Hcy-NH2, generating both near-infrared fluorescence and photoacoustic signals for monitoring the apoptosis process. The excellent "theranostic correlation" between the imaging signal and therapeutic response, as demonstrated in orthotopic breast tumors, highlights the potential of Cbl-DEVD-Hcy for effective tumor therapy and precise CDx in the body.

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