Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes.
OBJECTIVE
The objectives of this study are to investigate the toxicity associated with polycationic liposomes and to elucidate the underlying mechanism. We tested the hypothesis that the positive charge of liposomes is a key determinant of toxicity by testing differently charged liposomes in mice.


METHODS
Differently charged liposomal systems including cationic liposomes, LipofectAMINE and DOTAP, and neutral and negative liposomes were evaluated for their toxicity after pulmonary administration in mice. LDH assay and differential cell counts were performed to measure toxicity and pulmonary inflammation, respectively. Reactive oxygen intermediates (ROI) were assessed by chemiluminescence.


RESULTS
Instillation of cationic liposomes elicited dose-dependent toxicity and pulmonary inflammation. This effect was more pronounced with the multivalent cationic liposome LipofectAMINE as compared to the monovalent cationic DOTAP. Neutral and negative liposomes did not exhibit lung toxicity. Toxicity associated with cationic liposomes correlated with the oxidative burst induced by the liposomes. LipofectAMINE induced a dose-dependent increase in ROI generation. This effect was less pronounced with DOTAP and absent with neutral and negative liposomes.


CONCLUSIONS
ROI play a key role in cationic lipid-mediated toxicity. Polyvalent cationic liposomes cause a release of ROI which are responsible for the pulmonary toxicity.
Dokka
S
S
West Virginia University, Department of Basic Pharmaceutical Sciences, Morgantown 26506, USA.
Toledo
D
D
Shi
X
X
Castranova
V
V
Rojanasakul
Y
Y
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002412:Cations; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008081:Liposomes / Q000633:toxicity*; D008163:Luminescent Measurements; D008171:Lung Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009589:Nitrogen Oxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
D002412:Cations; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008081:Liposomes; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D007770:L-Lactate Dehydrogenase