Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage.
Intratracheal injection of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) complexes has been demonstrated to delay the onset and reduce the extent of ionizing irradiation-induced murine pulmonary organizing alveolitis/fibrosis. To facilitate translation of this modality to clinical fractionated radiotherapy, inhalation delivery of MnSOD-PL was developed using an ultrasonic nebulizer. Transgene product was quantitated by immunohistochemical quantitation and pulmonary tissue levels of MnSOD biochemical activity. C57BL/6NHsd female mice demonstrated a plasmid dose-dependent increased expression of MnSOD transgene product over the range of 250 microg-2.5 mg of MnSOD-PL administered over a constant 5 min interval. Delivery of a constant concentration of 500 microg of MnSOD-PL with varying times of administration ranging from 0.5 to 10 min demonstrated optimal MnSOD expression at 5 min. Mice pretreated by inhalation delivery of MnSOD-PL demonstrated significantly improved survival after 20 Gy single fraction irradiation to both lungs compared to LacZ-PL inhalation-treated or irradiated control mice. Mice receiving 10 fractions of 3.5 cGy demonstrated increased pulmonary MnSOD transgene product activity by a protocol of every Monday-Wednesday or daily inhalation of MnSOD-PL. Thus, inhalation radioprotective gene therapy using MnSOD-PL provides a practical and effective method for delivery of lung-specific radioprotection during fractionated radiotherapy protocols in a mouse model.
Carpenter
M
M
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Epperly
M W
MW
Agarwal
A
A
Nie
S
S
Hricisak
L
L
Niu
Y
Y
Greenberger
J S
JS
D000280:Administration, Inhalation; D000818:Animals; D004247:DNA / Q000008:administration & dosage*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D008081:Liposomes; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009330:Nebulizers and Vaporizers; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011878:Radiotherapy / Q000009:adverse effects*; D011879:Radiotherapy Dosage; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D014465:Ultrasonics
D008081:Liposomes; D004247:DNA; D013482:Superoxide Dismutase