Sonoporation Mediated Immunogene Therapy of Solid Tumors

Abstract Development of gene-based therapies for the treatment of inherited and acquired diseases, including cancer, has seen renewed interest in the use of nonviral vectors coupled to physical delivery modalities. Low-frequency ultrasound (US), with a well-established record in a clinical setting,...

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Veröffentlicht in:Ultrasound in medicine & biology 2010-03, Vol.36 (3), p.430-440
Hauptverfasser: Casey, Garrett, Cashman, James P, Morrissey, David, Whelan, Maria C, Larkin, John O, Soden, Declan M, Tangney, Mark, O'Sullivan, Gerald C
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Sprache:eng
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Zusammenfassung:Abstract Development of gene-based therapies for the treatment of inherited and acquired diseases, including cancer, has seen renewed interest in the use of nonviral vectors coupled to physical delivery modalities. Low-frequency ultrasound (US), with a well-established record in a clinical setting, has the potential to deliver DNA efficiently, accurately and safely. Optimal in vivo parameters for US-mediated delivery of naked plasmid DNA were established using the firefly luciferase reporter gene construct. Optimized parameters were used to administer a therapeutic gene construct, coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) and B7-1 costimulatory molecule, to growing murine fibrosarcoma tumors. Tumor progression and animal survival was monitored throughout the study and the efficacy of the US-mediated gene therapy determined and compared with an electroporation-based approach. Optimal parameters for US-mediated delivery of plasmid DNA to tumors were deduced to be 1.0 W/cm2 at 20% duty cycle for 5 min (60 J/cm2 ). In vivo US-mediated gene therapy resulted in a 55% cure rate in tumor-bearing animals. The immunological response invoked was cell mediated, conferring resistance against re-challenge and resistance to tumor challenge after transfer of splenocytes to naïve animals. US treatment was noninjurious to treated tissue, whereas therapeutic efficacy was comparable to an electroporation-based approach. US-mediated delivery of an immune-gene construct to growing tumors was therapeutically effective. Sonoporation has the potential to be a major factor in the development of nonviral gene delivery approaches. (E-mail: geraldc@iol.ie )
ISSN:0301-5629
1879-291X
DOI:10.1016/j.ultrasmedbio.2009.11.005