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

Abstract

Intratracheal injection of manganese superoxide dismutaseplasmid/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 mg-2.5 mg of MnSOD-PL administered over a constant 5 min interval. Delivery of a constant concentration of 500 mg 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. Gene Therapy (2005) 12, 685-693.

Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection

“…Previous studies have shown that chronic overproduction of ROS/RNS and subsequent pathological disease can be alleviated in a rodent model of radiation injury through overexpression of SOD [8,9]. Furthermore, it has been shown that manganese (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PYP 5+ , MnP) and other derivatives of SOD are effective radioprotectors [10][11][12][13][14].…”

Aerosolized STAT1 Antisense Oligodeoxynucleotides Decrease the Concentrations of Inflammatory Mediators in Bronchoalveolar Lavage Fluid in Bleomycin-Induced Rat Pulmonary Fibrosis

“…This approach presents a more promising method of therapy. Current therapeutic applications of ASON in lung diseases include asthma (15)(16)(17) and irradiation lung damage (12).…”

“…The mode of aerosolization was executed as previously described (12), and was ameliorated in this study. Briefly, to restrict rat movement, animals were confined in plastic bottle with the head extending from the top of the bottle.…”

The Effects of Aerosolized STAT1 Antisense Oligodeoxynucleotides on Rat Pulmonary Fibrosis

“…The mode of aerosolization was performed as previously described (16), and was ameliorated in this study. In brief, in order to restrict rat movement, the animals were confined in plastic bottles with the heads extending from the tops of the bottles.…”