Oxygen Radical-Mediated Pulmonary Toxicity Induced by Some Cationic Liposomes
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- Dokka, S., Toledo, D., Shi, X. et al. Pharm Res (2000) 17: 521. doi:10.1023/A:1007504613351
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Purpose. The objectives of this study are to investigate the toxicityassociated with polycationic liposomes and to elucidate the underlyingmechanism. We tested the hypothesis that the positive charge of liposomesis a key determinant of toxicity by testing differently chargedliposomes in mice.
Methods. Differently charged liposomal systems including cationicliposomes, LipofectAMINE and DOTAP, and neutral and negativeliposomes were evaluated for their toxicity after pulmonaryadministration in mice. LDH assay and differential cell counts were performedto measure toxicity and pulmonary inflammation, respectively. Reactiveoxygen intermediates (ROI) were assessed by chemiluminescence.
Results. Instillation of cationic liposomes eliciteddose-dependent toxicity and pulmonary inflammation. This effect was more pronouncedwith the multivalent cationic liposome LipofectAMINE as comparedto the monovalent cationic DOTAP. Neutral and negative liposomes didnot exhibit lung toxicity. Toxicity associated with cationic liposomescorrelated with the oxidative burst induced by the liposomes.LipofectAMINE induced a dose-dependent increase in ROI generation. Thiseffect was less pronounced with DOTAP and absent with neutral andnegative liposomes.
Conclusions. ROI play a key role in cationic lipid-mediated toxicity.Polyvalent cationic liposomes cause a release of ROI which areresponsible for the pulmonary toxicity.