Indo-Gem: An activatable theranostic prodrug, a "Turn-On" fluorescent probe, and a targetable imaging agent in the zebrafish gallbladder system.

Theranostics are crucial in both cancer diagnosis and targeted drug delivery, as they enable the simultaneous detection and treatment of disease within a single molecular or conjugated platform. However, theranostics is still facing challenges like real-time tracking for "where" prodrugs are activated in vivo, which poses a significant problem for molecule development. Organ-specific action to inspire the creation of innovative disease-curing technologies that are both accurate and efficient is still an underestimated task. We herein showcase the novel serendipitous gallbladder-targeting indole-based prodrug Indo-Gem for precise imaging-guided cancer therapy. Indo-Gem was prepared by an indole-malononitrile (dye) moiety, attached to the selected parent drug Gemcitabine via a disulfide cleavable linker. Indo-Gem is triggered by DTT with 27-fold fluorescent enhancement at pH 7.4, registering within 21 min. Unlike the most ignored adverse effects in prodrug activation, this indole-based dye targeting in a specific organ region of a zebrafish model via a combination of imaging ability and drug release. This is the first case that employs an indole-based moiety in prodrug design without any use of targeting ligands; the profound success of Indo-Gem and the well-defined mechanism suggest that the indole might serve as a scaffold to create novel therapeutic prodrugs with improved drug potency in future drug development.