Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response
- Authors: Bonnet, M. E., Erbacher, P., Bolcato-Bellemin, A. L.
- Year: 2008
- Journal: Pharm Res 25 2972-82
- Applications: in vivo / DNA, siRNA, STICKY SIRNA / in vivo-jetPEI
40 µg of nucleic acids were diluted in 100 µl of 5 % glucose solution. 6.4 µl of in vivo-jetPEI (N/P = 8) were diluted in 100 µl of 5 % glucose solution and mixed by vortexing for 10 sec. The in vivo-jetPEI solution was added to the nucleic acid solution, mixed by vortexing for 10 sec and incubated for at least 15 min at RT before IV injection in mice.
PURPOSE: The success of nucleic acid therapies depends upon delivery vehicle's ability to selectively and efficiently deliver therapeutic nucleic acids to target organ with minimal toxicity. The cationic polymer polyethylenimine (PEI) has been widely used for nucleic acid delivery due to its versatility and efficiency. In particular, the last generation of linear PEI (L-PEI) is being more efficient in vivo than the first generation of branched PEI. This led to several clinical trials including phase II bladder cancer therapy and human immunodeficiency virus immunotherapy. When moving towards to the clinic, it is crucial to identify potential side-effects induced by the delivery vehicle. MATERIALS AND METHODS: For this purpose we have analyzed the production of pro-inflammatory cytokines [tumor necrosis factor-alpha, interferon (IFN)-gamma, interleukin (IL)-6, IL-12/IL-23, IFN-beta and IL-1beta] and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase) in the blood serum of mice after systemic injection of DNA or siRNAs delivered with L-PEI. RESULTS: Our data show no major production of pro-inflammatory cytokines or hepatic enzymes after injection of DNA or oligonucleotides active for RNA interference (siRNAs or sticky siRNAs) complexed with L-PEI. Only a slight induction of IFN-gamma was measured after DNA delivery, which is probably induced by the CpG mediated response. CONCLUSION: Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.