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Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response

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Abstract

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-α, interferon (IFN)-γ, interleukin (IL)-6, IL-12/IL-23, IFN-β and IL-1β] 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-γ 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.

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Notes

  1. http://clinicaltrials.gov/ct2/results?spons=%22BioCancell+Therapeutics+Ltd%22&spons

  2. http://clinicaltrials.gov/ct2/show/NCT00270205?term=Phase+I%2FII+%28ACTG+5176%29&rank=1

Abbreviations

ALAT:

alanine aminotransferase

ALP:

alkaline phosphatase

ASAT:

aspartate aminotransferase

LDH:

Lactate dehydrogenase

L-PEI:

linear polyethylenimine

ssiRNA:

sticky siRNA

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Acknowledgments

These studies were supported by the sixth framework programme, EU-supported research, GIANT Integrated Project N°LSHB-CT-2004-512087 and RIGHT Integrated Project N°LSHB-CT-2004-005276. The authors want to thank Jeanne-Françoise Williamson for critical reading of the manuscript, Jean-Paul Behr for fruitful discussions and Fabrice Stock for the formulation of non-viral reagents.

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  1. Polyplus-transfection SA, Bioparc, BP90018, Boulevard Sébastien Brandt, 67401, Illkirch Cedex, France

    Marie-Elise Bonnet, Patrick Erbacher & Anne-Laure Bolcato-Bellemin

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  1. Marie-Elise Bonnet
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  2. Patrick Erbacher
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  3. Anne-Laure Bolcato-Bellemin
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Correspondence to Anne-Laure Bolcato-Bellemin.

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Bonnet, ME., Erbacher, P. & Bolcato-Bellemin, AL. Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response. Pharm Res 25, 2972–2982 (2008). https://doi.org/10.1007/s11095-008-9693-1

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  • DOI: https://doi.org/10.1007/s11095-008-9693-1

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