Sonoporation mediated immunogene therapy of solid tumors.
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/cm(2) at 20% duty cycle for 5 min (60 J/cm(2)). 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.
Cork Cancer Research Centre, Mercy University Hospital, University College Cork, Cork, Ireland.
Garrett
G
Casey
James P
JP
Cashman
David
D
Morrissey
Maria C
MC
Whelan
John O
JO
Larkin
Declan M
DM
Soden
Mark
M
Tangney
Gerald C
GC
O'Sullivan
D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D007167:Immunotherapy; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D010957:Plasmids / Q000235:genetics*; D013010:Sonication; D014463:Ultrasonography
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA