Aerosol gene therapy with PEI: IL-12 eradicates osteosarcoma lung metastases.
OBJECTIVE
We determined whether polyethylenimine (PEI), a polycationic DNA carrier, can be used to deliver the interleukin (IL) 12 gene by aerosol to treat established osteosarcoma (OS) lung metastases in a nude mouse model.


METHODS
Tumor response was assessed using our OS lung metastases model. Treatment with aerosolized PEI containing the murine IL-12 gene (PEI:IL-12; 600 microl PEI and 2 mg IL-12) was given twice weekly for 5-6 weeks.


RESULTS
Aerosol therapy for 2 weeks resulted in high expression of both the p35 and p40 subunits of IL-12 in the lungs but not in the livers of mice. Peak IL-12 mRNA expression was seen 24 h after a single aerosol PEI:IL-12 treatment. This expression gradually decreased with continued detection for up to 7 days. IL-12 protein was not detectable in plasma even after 6 weeks of aerosol therapy. The number of lung metastases in mice treated with aerosol PEI:IL-12 was decreased significantly (median, 0; range, 0-33) compared with mice that received PEI alone (median, 37.5; range, 11-125; P = 0.002). Nodule size was also significantly smaller in the aerosol PEI:IL-12 group with 87% of the nodules measuring <or=0.5 mm in diameter compared with 65% in the aerosol PEI group. Mice that received aerosol PEI alone had numerous large lung nodules (3-5 mm). In the aerosol PEI:IL-12 group, no nodules were >1 mm. Weekly aerosol PEI:IL-12 therapy was as effective as twice weekly therapy.


CONCLUSIONS
Aerosol therapy resulted in selective gene expression and protein production in the tumor area. Aerosol PEI:IL-12 may avoid the systemic toxicities described previously in patients treated with i.v. IL-12. Because OS metastasizes almost exclusively to the lung, aerosol PEI:IL-12 therapy may provide a therapeutic option, which may be especially valuable.
Jia
Shu-Fang
SF
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Worth
Laura L
LL
Densmore
Charles L
CL
Xu
Bo
B
Duan
Xiaoping
X
Kleinerman
Eugenie S
ES
D000336:Aerosols; D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000556:secondary / Q000628:therapy*; D011094:Polyethyleneimine / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection
D000336:Aerosols; D018664:Interleukin-12; D011094:Polyethyleneimine