Novel nanoparticle-combined therapy through EGFR and PD-L1 blockade: PFPR-siRNA-mediated suppressing NSCLC...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Advanced non-small cell lung cancer (NSCLC) treatments like EGFR-targeted therapy and immunotherapy face challenges due to drug resistance.
• Developing novel strategies to overcome resistance and improve therapeutic efficacy in NSCLC is critical.

Purpose of the Study:

• To investigate a novel nanoparticle system, PFPR (polydopamine-iron-polyethylenimine-Arg-Gly-Asp), for combined therapy against NSCLC.
• To evaluate the efficacy of PFPR nanoparticles delivering siRNA targeting EGFR and PD-L1 in blocking tumor progression and enhancing anti-tumor immunity.

Main Methods:

• PFPR nanoparticles were synthesized using polydopamine (PDA), iron ions, and RGD peptides to deliver siRNA targeting EGFR and PD-L1.
• In vitro studies assessed ROS production, cell death, proliferation, colony formation, and migration in NSCLC cells.
• In vivo studies used H1975 xenografts to evaluate tumor growth inhibition and immune cell modulation (CD3+CD8+ T cells, IFN-γ).
• Laser irradiation was used to activate photodynamic therapy (PDT) properties of the nanoparticles.

Main Results:

• PFPR nanoparticles, especially with laser treatment, significantly induced NSCLC cell death and suppressed proliferation, colony formation, and migration.
• PFPR-siRNA treatment upregulated pro-apoptotic markers (Bax, Caspase 3) and E-cadherin, while downregulating Cyclin D1 and N-cadherin.
• In vivo, PFPR-siRNA significantly reduced tumor weight and volume, with further reduction upon laser irradiation.
• PFPR-siPD-L1 therapy enhanced cytotoxic activity by increasing CD3+CD8+ T cells and IFN-γ levels.

Conclusions:

• The PFPR nanoparticle system effectively suppresses NSCLC progression through synergistic photodynamic therapy (PDT) and blockade of EGFR and PD-L1.
• This novel approach holds potential for overcoming therapeutic drug resistance in advanced NSCLC by activating anti-tumor immunity.