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.