A copper-based ascorbic acid-activatable gel for postoperative glioblastoma therapy.

Area of Science:

• Biomaterials Science
• Cancer Therapy
• Immunology

Background:

• Glioblastoma (GBM) rapidly recurs post-surgery due to invasive growth and immunosuppression.
• Current treatments struggle to address residual tumor cells and the tumor microenvironment.
• Novel therapeutic strategies are needed for effective GBM postoperative management.

Purpose of the Study:

• To develop an implantable gel (CuTR-gel) for postoperative GBM therapy.
• To create a system responsive to endogenous ascorbic acid (AA) for controlled drug release.
• To combine direct tumoricidal effects with immune activation for preventing GBM recurrence.

Main Methods:

• Developed an ascorbic acid (AA)-responsive hydrogel crosslinked by copper ions (CuTR-gel).
• Co-delivered TPD-Cu (AA-activated prodrug) and R848 (TLR7/8 agonist) within the gel.
• Utilized sodium alginate (SA) for copper chelation and controlled drug release kinetics.
• Investigated the in situ formation of cytotoxic Cu(DTC)2 and immunogenic cell death (ICD) induction.

Main Results:

• Endogenous AA triggered TPD-Cu cleavage, releasing diethyldithiocarbamate (DTC).
• DTC formed cytotoxic Cu(DTC)2, causing tumor cell death and initiating ICD.
• Copper dissociation from the gel enabled controlled release of R848, enhancing anti-tumor immunity.
• CuTR-gel demonstrated sustained drug release, immediate cytocidal effects, and durable immune activation.

Conclusions:

• CuTR-gel provides a dual-action strategy for postoperative GBM treatment.
• The system effectively targets residual GBM cells and modulates the tumor microenvironment.
• This approach shows significant potential for preventing long-term GBM recurrence through sustained immune response.