Sonoporation mediated immunogene therapy of solid tumors

Area of Science:

• Biomedical Engineering
• Gene Therapy
• Oncology

Background:

• Gene therapy development is exploring nonviral vectors combined with physical delivery for inherited and acquired diseases.
• Low-frequency ultrasound (US) is a clinically established modality with potential for efficient, accurate, and safe DNA delivery.

Purpose of the Study:

• To establish optimal in vivo parameters for US-mediated delivery of naked plasmid DNA.
• To evaluate the therapeutic efficacy of US-mediated gene therapy using a granulocyte-macrophage colony-stimulating factor (GM-CSF) and B7-1 construct in murine fibrosarcoma tumors.

Main Methods:

• Optimized parameters for US-mediated DNA delivery were determined using a firefly luciferase reporter gene.
• Therapeutic gene constructs were administered to tumors using optimized US parameters (1.0 W/cm(2), 20% duty cycle, 5 min).
• Tumor progression, animal survival, and immunological responses were monitored; efficacy was compared to electroporation.

Main Results:

• Optimal US parameters for DNA delivery to tumors were identified as 1.0 W/cm(2) at 20% duty cycle for 5 min (60 J/cm(2)).
• In vivo US-mediated gene therapy achieved a 55% cure rate in tumor-bearing animals.
• The treatment induced a cell-mediated immunological response, conferring resistance to tumor re-challenge.

Conclusions:

• US-mediated delivery of an immune-gene construct to growing tumors is therapeutically effective.
• The US approach was noninjurious to treated tissue and showed comparable efficacy to electroporation.
• Sonoporation presents significant potential as a key nonviral gene delivery method for future therapeutic applications.