Bonnet Marie-Elise, Erbacher Patrick, Bolcato-Bellemin Anne-Laure
Polyplus-transfection SA, Bioparc, BP90018, Boulevard Sébastien Brandt, Illkirch Cedex, France.
Pharm Res. 2008 Dec;25(12):2972-82. doi: 10.1007/s11095-008-9693-1. Epub 2008 Aug 16.
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.
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.
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.
Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.
核酸疗法的成功取决于递送载体能否以最小的毒性将治疗性核酸选择性且高效地递送至靶器官。阳离子聚合物聚乙烯亚胺（PEI）因其多功能性和高效性已被广泛用于核酸递送。特别是，新一代线性PEI（L-PEI）在体内比第一代支链PEI更高效。这引发了多项临床试验，包括II期膀胱癌治疗和人类免疫缺陷病毒免疫疗法。在迈向临床应用时，识别递送载体引起的潜在副作用至关重要。
为此，我们分析了用L-PEI递送DNA或小干扰RNA（siRNA）后，小鼠血清中促炎细胞因子[肿瘤坏死因子-α、干扰素（IFN）-γ、白细胞介素（IL）-6、IL-12/IL-23、IFN-β和IL-1β]的产生以及肝酶水平（丙氨酸转氨酶、天冬氨酸转氨酶、乳酸脱氢酶和碱性磷酸酶）。
我们的数据显示，注射与L-PEI复合的DNA或对RNA干扰有活性的寡核苷酸（siRNA或粘性siRNA）后，促炎细胞因子或肝酶没有大量产生。DNA递送后仅检测到IFN-γ有轻微诱导，这可能是由CpG介导的反应引起的。
综合我们的数据表明，线性聚乙烯亚胺是核酸治疗的首选递送试剂。
