ROS-triggered and regenerating anticancer nanosystem: an effective strategy to subdue tumor's multidrug resistance

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Tumor microenvironment (TME) variability poses challenges for drug delivery systems targeting cancer.
• Stimuli-responsive nanosystems often face reduced efficacy due to inconsistent TME triggers.
• Multidrug resistance (MDR) remains a significant hurdle in effective cancer treatment.

Purpose of the Study:

• To develop a novel reactive oxygen species (ROS) triggered nanosystem capable of self-sustaining ROS levels within the TME.
• To enhance drug delivery and overcome MDR by utilizing a ROS-regenerating mechanism.
• To improve tumor targeting and therapeutic outcomes in preclinical cancer models.

Main Methods:

• Synthesis of a unique amphiphilic polymer (TBH) comprising D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA), and an arylboronic ester linker.
• Design of a ROS-triggered nanosystem that degrades upon ROS exposure, releasing TPGS and regenerating ROS.
• Loading of doxorubicin (DOX) into the nanosystem (DOX-TBH) for evaluating drug delivery and therapeutic efficacy.
• In vitro studies using MCF-7/ADR cells and in vivo studies using xenografted tumor tissues to assess ROS regeneration, drug cytotoxicity, and tumor inhibition.

Main Results:

• The TBH nanosystem demonstrated efficient ROS-triggered disassembly and release of TPGS.
• TPGS induced ROS regeneration via interaction with mitochondrial respiratory complex II in cancer cells and tumor tissues.
• DOX-TBH exhibited enhanced cytotoxicity due to ROS-mediated drug release and P-gp inhibition by TPGS.
• HA conjugation significantly improved the tumor targeting of DOX-TBH.
• The ROS-based triggering and regenerating mechanism led to marked inhibition of tumor growth in vivo.

Conclusions:

• The developed ROS-triggered and regenerating nanosystem offers a promising strategy to overcome TME variability and MDR.
• TPGS plays a dual role in ROS generation and P-gp inhibition, enhancing chemotherapeutic efficacy.
• The combination of HA for tumor targeting and the ROS-responsive system provides a robust platform for advanced cancer drug delivery.