Acidity-responsive nanoplatforms aggravate tumor hypoxia via multiple pathways for amplified chemotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Hypoxia tumor microenvironment (TME) limits cancer therapy effectiveness, promoting recurrence and metastasis.
• Vascular embolization can worsen intratumoral hypoxia, a challenge in cancer treatment.
• Hypoxia-activated prodrugs (HAPs) show enhanced efficacy in hypoxic conditions, suggesting combination strategies.

Purpose of the Study:

• To develop an acidity-responsive nanoplatform (TACC NP) for enhanced hypoxia-activated chemotherapy.
• To combine tumor embolization, photodynamic therapy, and HAP chemotherapy for synergistic cancer treatment.
• To investigate the therapeutic effects and biosafety of TACC NPs in vivo.

Main Methods:

• Constructed TACC NPs by loading Chlorin e6 (Ce6), thrombin (Thr), and AQ4N into calcium phosphate nanocarriers.
• Utilized an acidity-responsive system that degrades in the acidic TME to release Thr and Ce6.
• Applied laser irradiation to induce photodynamic effects and trigger vessel destruction and oxygen consumption.

Main Results:

• TACC NPs effectively degraded in the acidic TME, releasing Thr and Ce6.
• Laser irradiation in combination with released agents led to tumor vessel destruction and aggravated intratumoral hypoxia.
• Enhanced chemotherapeutic effect of AQ4N was observed due to increased hypoxia.
• In vivo fluorescence imaging confirmed synergistic therapeutic effects and good biosafety.

Conclusions:

• The developed TACC NP is an effective acidity-responsive nanoplatform for multi-pathway hypoxia-activated chemotherapy.
• The combination of tumor embolization, photodynamic therapy, and prodrug chemotherapy demonstrates significant synergistic therapeutic effects.
• TACC NPs show promise for advanced cancer therapy with good biosafety.