Catalytic ROS-Amplifying Self-Immolative Linkers Enable Carrier-Free Prodrugs for Refractory Tumors.

Area of Science:

• Medicinal Chemistry
• Drug Delivery
• Oncology

Background:

• Tumor redox-buffering systems confer chemoresistance.
• Existing ROS-responsive prodrug linkers have limitations including oxidant consumption, low sensitivity, and complex formulations, hindering clinical application.

Purpose of the Study:

• To design and evaluate a novel phenylselanyl cyclohexenone self-immolative linker for ROS-triggered prodrug activation with built-in redox amplification.
• To assess the efficacy of prodrugs utilizing this linker in various cancer models.

Main Methods:

• Synthesis of a phenylselanyl cyclohexenone self-immolative linker.
• Incorporation of the linker into carrier-free prodrugs with chemotherapeutics and small-molecule inhibitors.
• Evaluation of prodrug activation, biodistribution, systemic toxicity, and antitumor activity in vitro and in vivo across breast cancer, pancreatic ductal adenocarcinoma, and leukemia models.

Main Results:

• The linker enables ROS-triggered cleavage and releases a redox-active selenium species that amplifies oxidative stress via a GSH-dependent cycle.
• Prodrugs demonstrated stability in neutral media and efficient activation by endogenous ROS.
• Improved biodistribution, reduced systemic toxicity, and enhanced antitumor activity were observed in multiple cancer models.

Conclusions:

• The developed ROS-amplifying self-immolative linker offers a modular strategy to overcome redox-associated drug resistance.
• This approach enhances the translational potential of small-molecule prodrugs for cancer therapy.