Purpose, The objectives of this study are to investigate the toxicity assoc
iated with polycationic liposomes and to elucidate the underlying mechanism
. We tested the hypothesis that the positive charge of liposomes is a key d
eterminant of toxicity by testing differently charged liposomes in mice.
Methods. Differently charged liposomal systems including cationic liposomes
, LipofectAMINE acid DOTAP, and neutral and negative liposomes were evaluat
ed 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 assess
ed by chemiluminescence.
Results. Instillation of cationic liposomes elicited dose-dependent toxicit
y and pulmonary inflammation. This effect was more pronounced with the mult
ivalent cationic liposome LipofectAMINE as compared to the monovalent catio
nic DOTAP. Neutral and negative liposomes did not exhibit lung toxicity. To
xicity associated with cationic liposomes correlated with the oxidative bur
st induced by the liposomes. LipofectAMINE induced a dose-dependent increas
e 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. Polyv
alent cationic liposomes cause a release of ROI which are responsible for t
he pulmonary toxicity.