Intratracheal administration of interleukin 12 plasmid-cationic lipid complexes inhibits murine lung metastases

Hum Gene Ther. 1999 Mar 20;10(5):723-31. doi: 10.1089/10430349950018481.

Abstract

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.

MeSH terms

  • Animals
  • Female
  • Green Fluorescent Proteins
  • Interferon-gamma / therapeutic use
  • Interleukin-12 / administration & dosage*
  • Interleukin-12 / genetics*
  • Lipids / administration & dosage*
  • Liposomes / therapeutic use
  • Luminescent Proteins / metabolism
  • Lung / metabolism
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Models, Genetic
  • Plasmids
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Lipids
  • Liposomes
  • Luminescent Proteins
  • Green Fluorescent Proteins
  • Interleukin-12
  • Interferon-gamma