Rational Development of Activatable Prodrugs of the GSTP1 Inhibitor NBDHEX: Turn-On NIR Fluorogenic Drug Delivery...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Glutathione-S-transferase pi (GSTP1) is overexpressed in cancer cells and inactivates anticancer drugs.
• NBDHEX is a potent GSTP1 inhibitor but has poor solubility and bioavailability.
• Developing targeted drug delivery systems is crucial for improving cancer therapy.

Purpose of the Study:

• To design and synthesize a reactive oxygen species (ROS)-responsive fluorogenic prodrug of NBDHEX.
• To evaluate the prodrug's efficacy in inhibiting GSTP1 and its anticancer activity.
• To assess the prodrug's activation mechanism, fluorescence properties, and in vivo safety.

Main Methods:

• Synthesis of the ROS-responsive prodrug RK-251 by conjugating NBDHEX with a QCy7 fluorophore and a ROS-sensitive unit.
• In vitro evaluation of GSTP1 inhibition, ROS-mediated drug release, and anticancer activity against cancer cell lines.
• In vivo studies using zebrafish embryos to assess fluorescence imaging and toxicity.

Main Results:

• RK-251 demonstrated ROS-mediated uncaging of NBDHEX with turn-on NIR fluorescence and potent GSTP1 inhibition.
• The prodrug exhibited significant anticancer activity against triple-negative breast cancer cells.
• In vivo studies in zebrafish confirmed endogenous ROS-mediated activation and QCy7 release without toxicity.

Conclusions:

• RK-251 is an effective ROS-responsive fluorogenic prodrug for targeted cancer therapy.
• The prodrug offers a dual modality of therapeutic action and fluorescence imaging.
• RK-251 shows translational potential for cancer treatment and diagnostics.