Benzyl-Spacer-Engineered Prodrug: Enabling NIR Fluorescent Activation for Cancer Therapy in a Zebrafish Gallbladder Model

A novel
near-infrared (NIR) prodrug, INM-Gem, was
synthesized and characterized, which significantly improves the application
of our previous molecular design for cancer therapy and diagnostics.
Selective drug activation in tumor microenvironments via 1,6-elimination
is enabled by the incorporation of a benzyl linker. Comparative studies
reveal that our probe (i) is allowed to penetrate deeper into tissue
(zebrafish), (ii) has less background signal interference, and (iii)
involves greater specificity in biological systems than its predecessor.
Chemical activation concurrently liberates gemcitabine and triggers
NIR “turn-on” fluorescence at 673 nm (Stokes shift:
131 nm), facilitating sensitive, real-time drug-release monitoring.
The dual-drug delivery and imaging functionality establish INM-Gem as a robust platform for precise bioimaging and targeted therapy.
This work highlights the additional potential of a benzyl spacer in
theranostics, wherein the cleavable linker helps enable this NIR-responsive
modality for biomedical research.