Intratracheal administration of interleukin 12 plasmid-cationic lipid complexes inhibits murine lung metastases.
Administration of plasmid/lipid complexes to the lung airways for the treatment of metastatic pulmonary diseases represents a new strategy of gene therapy. In this study we present evidence that intratracheal administration of a plasmid encoding murine IL-12 complexed with N-[1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride:cholesterol inhibits the growth of lung metastases, using a renal cell carcinoma model. Instillation of pIL-12/lipid complexes resulted in expression of biologically active IL-12 (170-240 pg/ml) and IFN-gamma (100-190 pg/ml) in the bronchoalveolar lavage fluid. A significantly reduced number of lung metastases (26+/-24) was observed in mice instilled with IL-12/lipid complexes 24 hr after tumor challenge, whereas more than 250 metastatic foci were counted in lungs of untreated mice. Moreover, IL-12/lipid inhibited the growth of 3-day-old established metastases when compared with empty plasmid/lipid or IL-12 plasmid in saline. Mice receiving IL-12 gene therapy survived significantly longer (median survival of 43 days) than untreated mice (median survival of 31 days) or mice treated with control plasmid/lipid complexes (median survival of 35 days). These data demonstrate that a nonviral IL-12 gene therapy employing synthetic cationic lipids as a delivery system can be used to inhibit the development of lung metastases. Thus, this method provides support for the use of IL-12/lipid complexes to control the growth of pulmonary metastases and represents a potentially safer alternative to IL-12 protein immunotherapy.
Blezinger
P
P
GeneMedicine, Inc., The Woodlands, TX 77381-4248, USA.
Freimark
B D
BD
Matar
M
M
Wilson
E
E
Singhal
A
A
Min
W
W
Nordstrom
J L
JL
Pericle
F
F
D000818:Animals; D005260:Female; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma / Q000627:therapeutic use; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000235:genetics*; D008055:Lipids / Q000008:administration & dosage*; D008081:Liposomes / Q000627:therapeutic use; D008164:Luminescent Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008957:Models, Genetic; D010957:Plasmids; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D008055:Lipids; D008081:Liposomes; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D018664:Interleukin-12; D007371:Interferon-gamma