Sequential injection of cationic liposome and plasmid DNA effectively transfects the lung with minimal inflammatory toxicity.
A major hurdle to lipoplex-based systemic gene delivery is acute inflammatory toxicity. In this study, a safe, simple, and effective alternative to lipoplex administration, specifically, sequential injection of cationic liposome and plasmid DNA, was evaluated. When plasmid DNA was injected into the tail vein of mice 2-5 min after the injection of cationic liposomes, 50-80% lower levels of proinflammatory cytokines, including TNF-alpha, IL-12, and IFN-gamma, were observed compared to lipoplex injection. The sequential injection technique yielded a two- to fivefold higher level of transgene expression in the lung and was more effective in repeated dosing than lipoplex. Other types of lipoplex-associated toxicities, such as neutropenia, lymphopenia, thrombocytopenia, and complement depletion, were also significantly reduced with sequential injection. The reduction in cytokine release was observed with several different liposome formulations and appeared to be a general phenomenon.
Tan
Y
Y
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Liu
F
F
Li
Z
Z
Li
S
S
Huang
L
L
D000818:Animals; D003176:Complement C3 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008081:Liposomes / Q000378:metabolism* / Q000633:toxicity; D008168:Lung / Q000378:metabolism*; D051379:Mice; D010957:Plasmids / Q000235:genetics* / Q000633:toxicity; D013997:Time Factors; D014162:Transfection / Q000379:methods*; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D003176:Complement C3; D016207:Cytokines; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D003907:Dexamethasone; D007371:Interferon-gamma