Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response
Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response
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DOI：
10.1007/s11095-008-9693-1
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发表时间：
2008-12-01
影响因子：
3.7
通讯作者：
Bolcato-Bellemin, Anne-Laure
中科院分区：
文献类型：
--
作者：
Bonnet, Marie-Elise;Erbacher, Patrick;Bolcato-Bellemin, Anne-Laure
核酸疗法的成功取决于递送载体以最小毒性选择性和有效地将治疗性核酸递送至靶器官的能力。阳离子聚合物聚乙烯亚胺（PEI）由于其多功能性和效率而被广泛用于核酸递送。特别地，最后一代线性PEI（L-PEI）在体内比第一代支化PEI更有效。这导致了一些临床试验，包括第二阶段膀胱癌治疗和人类免疫缺陷病毒免疫治疗。在走向临床的过程中，识别由递送载体引起的潜在副作用至关重要，为此，我们分析了促炎细胞因子[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-1 β]的产生和肝酶水平（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，在全身注射用L-PEI递送的DNA或siRNA后，在注射与L-PEI复合的对RNA干扰有活性的DNA或寡核苷酸（siRNA或粘性siRNA）后，这些细胞因子或肝酶的活性降低。在DNA递送后仅测量到IFN-γ的轻微诱导，这可能是由CpG介导的respons. Together诱导的，我们的数据突出显示线性聚乙烯亚胺是核酸治疗的选择递送试剂。
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-1 beta] 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.