Modification-Response Integrated Modules Driven Cyclization-Dependent Prodrug Self-Assembly for Reshaping...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Chemotherapy efficacy is limited by complex tumor redox microenvironments.
• Prodrug nanoassemblies offer a strategy to enhance therapeutic outcomes.
• Tumor redox homeostasis is a key target for cancer therapy.

Purpose of the Study:

• To develop novel cyclic chalcogenide-linked paclitaxel prodrug nanoassemblies.
• To investigate the tumor site-specific activation and redox homeostasis modulation of these nanoassemblies.
• To evaluate their potential in enhancing paclitaxel's antitumor effects.

Main Methods:

• Fabrication of five-membered cyclic diselenide and disulfide-linked paclitaxel prodrugs.
• Integration of modification and response modules within the nanoassemblies.
• Assessment of inhibition of the glutathione-glutathione peroxidase (GSH/GPx) antioxidant system.
• Measurement of reactive oxygen species (ROS) generation and mitochondrial membrane potential.
• Evaluation of tumor cell apoptosis and synergistic antitumor effects.

Main Results:

• The nanoassemblies achieved tumor site-specific activation.
• They effectively blocked the GSH/GPx antioxidant system and amplified ROS generation.
• This reshaping of redox homeostasis induced mitochondrial membrane potential loss and apoptosis in tumor cells.
• Synergistic potentiation of paclitaxel's antitumor effects was observed.

Conclusions:

• The developed intelligent prodrug nanoplatform shows significant potential for advanced antitumor nanomedicines.
• This approach offers new perspectives for overcoming chemotherapy resistance.
• The findings highlight the clinical research value of targeting tumor redox homeostasis.