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

Administration of plasmid/lipid complexes to the lung airways for the treat ment of metastatic pulmonary diseases represents a new strategy of gene the rapy. In this study we present evidence that intratracheal administration o f a plasmid encoding murine IL-12 complexed with N-(1-(2,3-dioleyloxy)propy l)-N,N,N-trimethylammonium chloride:cholesterol inhibits the growth of lung metastases, using a renal cell carcinoma model, Instillation of pIL-12/lip id complexes resulted in expression of biologically active IL-12 (170-240 p g/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, whe reas more than 250 metastatic foci were counted in lungs of untreated mice. Moreover, IL-12/lipid inhibited the growth of 3-day-old established metast ases when compared with empty plasmid/lipid or IL-12 plasmid in saline. Mic e receiving IL-12 gene therapy survived significantly longer (median surviv al of 43 days) than untreated mice (median survival of 31 days) or mice tre ated with control plasmid/lipid complexes (median survival of 35 days), The se 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-1 2/lipid complexes to control the growth of pulmonary metastases and represe nts a potentially safer alternative to IL-12 protein immunotherapy.