Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity.
Inflammatory toxicity represents a typical toxicity associated with systemic administration of cationic liposome/DNA complex (lipoplex). Collected information indicates that the lipoplex gene delivery system mediates an uptake of plasmid DNA by the liver, mainly by Kupffer cells, in which a large amount of cytokine is produced. Therefore, many efforts have been made to overcome this problem. Previous reports by our laboratory demonstrated that sequential injection of cationic liposome and DNA could dramatically decrease the toxicity. In comparison with lipoplex injection, this method significantly suppresses the uptake of DNA by the liver. Opsonization effect in the stimulation of Kupffer cell uptake is proposed as an explanation for the differences in the pharmacokinetic properties of plasmid DNA after lipoplex injection and sequential injection. In this review, we cover the current understanding of the mechanisms underlying inflammatory toxicity and the several attempts to overcome this toxicity. The mechanism related to the pharmacokinetic properties of the lipoplex is focused on here for discussion.
Zhang
Jing-Shi
JS
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Liu
Feng
F
Huang
Leaf
L
D000818:Animals; D004247:DNA / Q000493:pharmacokinetics* / Q000633:toxicity*; D018014:Gene Transfer Techniques / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008081:Liposomes / Q000493:pharmacokinetics* / Q000633:toxicity*
D008081:Liposomes; D004247:DNA