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

被引：68

作者：

Carpenter, M ^{[1
]}

Epperly, MW ^{[1
]}

Agarwal, A ^{[1
]}

Nie, S ^{[1
]}

Hricisak, L ^{[1
]}

Niu, Y ^{[1
]}

Greenberger, JS ^{[1
]}

机构：

[1] Univ Pittsburgh, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA 15213 USA

来源：

GENE THERAPY | 2005年 / 12卷 / 08期

关键词：

radiation protection; inhalation gene therapy; MnSOD;

D O I：

10.1038/sj.gt.3302468

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu g - 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.

引用

页码：685 / 693

页数：9

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