Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

Gene Ther. 2005 Apr;12(8):685-93. doi: 10.1038/sj.gt.3302468.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Inhalation
  • Animals
  • DNA / administration & dosage*
  • Female
  • Gene Expression
  • Genetic Therapy / methods*
  • Immunohistochemistry / methods
  • Liposomes
  • Lung / enzymology
  • Lung / metabolism
  • Lung / radiation effects*
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Nebulizers and Vaporizers
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / prevention & control*
  • Radiotherapy / adverse effects*
  • Radiotherapy Dosage
  • Superoxide Dismutase / analysis
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Transgenes
  • Ultrasonics

Substances

  • Liposomes
  • DNA
  • Superoxide Dismutase