Single-dose in situ storage for intensifying anticancer efficacy via combinatorial strategy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Metronomic chemotherapy can improve the tumor microenvironment (TME) and immunotherapy but requires continuous low-dose drug administration and faces rapid clearance.
• Developing strategies for sustained drug delivery and immune stimulation within the tumor is crucial for effective cancer treatment.

Purpose of the Study:

• To develop a single-dose in situ immune stimulator storage for prolonged drug retention and sustained release in the tumor parenchyma.
• To investigate the potential of this storage to initiate immune responses via photothermal therapy (PTT) and remodel the immunosuppressive TME.
• To evaluate the synergistic effects of paclitaxel-loaded storage (NGOPC@PTX) with PTT in enhancing antitumor immunity.

Main Methods:

• Fabrication of NGOPC nanostructures (~60 nm) from modified nano graphene oxide (NGO-PEG-pep and NGO-PEG-CABT) for deep tumor penetration.
• In situ network formation triggered by TME-specific legumain for enhanced drug retention.
• Loading of paclitaxel (PTX) into NGOPC@PTX to block immunologic escape.
• Assessment of antitumor immunological efficacy, including HSP70-mediated cell death, regulatory T cell reduction, and cytotoxic T lymphocyte activation.

Main Results:

• NGOPC@PTX demonstrated superior accumulation in tumors and significant antitumor immunological efficacy.
• The treatment successfully induced HSP70-mediated immunogenic cell death and activated cytotoxic T lymphocytes.
• A notable reduction in regulatory T cells was observed, contributing to a more favorable immune microenvironment.
• Combined PTT and NGOPC@PTX treatment exhibited excellent tumor growth inhibition and prolonged animal lifespan.

Conclusions:

• The developed in situ storage system effectively achieves prolonged drug retention and sustained release, remodeling the TME.
• The combination of NGOPC@PTX and PTT synergistically enhances antitumor immunity through multiple mechanisms.
• This innovative approach holds significant potential for intensified cancer immunotherapy and improved patient outcomes.