Oligonucleotide decoy to NF-κB slowly released from PLGA microspheres reduces chronic inflammation in rat
Oligonucleotide decoy to NF-κB slowly released from PLGA microspheres reduces chronic inflammation in rat
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DOI：
10.1016/j.phrs.2009.03.012
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发表时间：
2009-07-01
影响因子：
9.3
通讯作者：
Carnuccio, Rosa
中科院分区：
文献类型：
--
作者：
De Stefano, Daniela;De Rosa, Giuseppe;Carnuccio, Rosa
核因子κ B （nf - κ B）在参与免疫和炎症过程的几个基因的表达中起关键作用。之前，我们证明了NF-kappa B的激活可以被双链寡脱氧核苷酸（ODN）显著抑制。然而，ODN的治疗用途需要一种能够改善细胞膜交叉不良和快速体内酶降解的递送系统。聚（D， l -丙交酯-羟基乙酸酯）（PLGA）微球可以提高ODN在生物环境中的稳定性，并能在较长时间内释放包膜药物。在这里，我们使用了一个针对NF-kappa B的诱饵ODN，并研究了它在裸形式给药或通过PLGA微球递送时的效果。在慢性炎症的大鼠模型中。皮下植入角菜胶浸泡海绵后，白细胞浸润和肉芽组织的形成被释放诱饵ODN的微球共同注射抑制长达15天，而裸诱饵ODN的这种影响仅持续5天。对肉芽组织进行的分子分析表明，抑制NF-kappa B的激活与肿瘤坏死因子- α (tnf - α)和诱导型一氧化氮合酶（iNOS）表达的降低有关。我们的研究结果表明，微球可能是改善诱饵ODN药代动力学的有用工具，并且可能是抑制慢性炎症中nf - κ B激活的一种策略。2009爱思唯尔有限公司所有航班预订。
Nuclear factor-kappa B (NF-kappa B) plays a key role in the expression of several genes involved in the immune and inflammatory process. Previously, we demonstrated that NF-kappa B activation can be significantly inhibited by a double stranded oligodeoxynucleotide (ODN). Nevertheless, the therapeutic use of ODN requires a delivery system able to improve poor crossing of cell membranes and rapid in vivo enzymatic degradation. Poly(D,L-lactide-co-glycolide) (PLGA) microspheres can increase ODN stability in biological environment and release the encapsulated drug in long time frames. Here, we used a decoy ODN against NF-kappa B and we investigated its effect, when administered in naked form or when delivered by PLGA micropsheres. in a rat model of chronic inflammation. The subcutaneous implant of lambda-carrageenin-soaked sponges caused leukocyte infiltration and formation of granulation tissue which were inhibited up to 15 days by co-injection of microspheres releasing decoy ODN whereas naked decoy ODN showed this effect only up to 5 days. Molecular analysis performed on granulation tissue demonstrated an inhibition of NF-kappa B activation correlated to a decrease of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression. Our results suggest that microspheres could be an useful tool to improve pharmacokinetics of decoy ODN and may represent a strategy to inhibit NF-kappa B activation in chronic inflammation. (C) 2009 Elsevier Ltd. All Fights reserved.