Side-effects of a systemic injection of linear polyethylenimine-DNA complexes.
BACKGROUND
Systemic administration of linear polyethylenimine-DNA complexes (L-PEI/DNA) results in transient expression of the transgene in the lung. This study analyzes the side-effects associated with L-PEI-mediated transfection.


METHODS
Mice weighing from 16 to 25 g received increasing amounts of L-PEI/DNA intravenously. Gene expression was evaluated using luciferase as a reporter gene. Toxicity was evaluated by monitoring the appearance of shock after injection, the survival of the animals, and the microscopic damage in the tissues. Adherence of blood cells and endothelium activation were observed after CD11-b and von Willebrand immunostaining. Anti-aggregant treatments were used in order to prevent the formation of thrombi.


RESULTS
Increasing the quantity of L-PEI/DNA resulted in a marked augmentation of the luciferase activity in the lung, but was associated with liver necrosis and death. Lethality was reached at lower doses in older mice, suggesting an age influence. Transfection was associated with activation of the lung endothelium and increased adhesion of small aggregates containing platelets and CD11-b-positive cells, without the appearance of large thrombi and of lung injury. Anti-aggregant treatments (aspirin, EDTA, heparin or clopidogrel) decreased the L-PEI-mediated transfection, supporting the hypothesis that platelets participate in the blocking of DNA complexes in the lung capillaries.


CONCLUSIONS
This study demonstrates that L-PEI/DNA activates the lung endothelium and forms small aggregates, a side-effect linked to the transfection efficiency.
Chollet
Patrice
P
Lung Cancer Research Group, EMI INSERM 9924, Institut Albert Bonniot, Domaine de la Merci, 38706 La Tronche, France.
Favrot
Marie C
MC
Hurbin
A
A
Coll
Jean-Luc
JL
D000818:Animals; D004247:DNA / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D015316:Genetic Therapy / Q000009:adverse effects; D008156:Luciferases; D008168:Lung / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011094:Polyethyleneimine / Q000009:adverse effects* / Q000627:therapeutic use; D012769:Shock / Q000139:chemically induced; D014162:Transfection
D011094:Polyethyleneimine; D004247:DNA; D008156:Luciferases