Development of pH/Glutathione-Responsive Theranostic Agents Activated by Glutathione S‑Transferase π for Human Colon Cancer

Two
novel theranostic agents HJTA and HJTB have
been designed and synthesized by covalently linking a β-carboline
derivative, with antitumor activities and pH-responsive fluorescence,
with a 2-exomethylenecyclohexanone moiety, which can be activated
by the tumor-targeting glutathione (GSH)/glutathione S-transferase
π (GSTπ). These agents showed pH- and GSH-dual-responsive
fluorescence in tumor cells but not in normal cells. Importantly, HJTA selectively illuminated tumor tissue for up to 7 h and
generated precise visualization of orthotopic colonic tumors through
the blood circulation system in intraoperative mice. Furthermore, HJTA exhibited potent and selective antiproliferative activities
and colonic tumor inhibition in mice. Finally, HJTA induced
great cancer cell apoptosis and autophagy by regulating the expression
of apoptotic and autophagic proteins. Therefore, this pH/GSH-dual-responsive
fluorescent probe with cancer-targeting therapeutic activity provides
a novel tool for precise diagnosis and tumor treatment, therefore
broadening the impact of multifunctional agents as theranostic precision
medicines.