Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment
Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment
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DOI：
10.1038/mt.2009.208
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Sepp-Lorenzino, Laura
中科院分区：
文献类型：
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作者：
Abrams, Marc T.;Koser, Martin L.;Sepp-Lorenzino, Laura
尽管最近取得了进展，但全身递送仍然是开发安全有效的基于小抑制性RNA（siRNA）的治疗剂的主要障碍。将siRNA包封到脂质体中是克服诸如在血清中的低稳定性和靶细胞的低效内化的障碍的有希望的选择。然而，脂质体的主要缺点是可能诱导急性炎症反应，从而增加许多不良反应的风险。在这项研究中，我们表征了脂质体siRNA递送载体LNP 201，其能够使小鼠肝脏中的mRNA靶点沉默超过80%。描述了LNP 201的生物分布特征、单次和多次给药后的功效、作用机制和炎症毒性。此外，我们证明了糖皮质激素受体（GR）激动剂地塞米松（Dex）抑制LNP 201诱导的细胞因子释放，炎症基因诱导，和丝裂原活化蛋白激酶（MAPK）磷酸化在多种组织。这些数据提供了一种可能的临床策略，用于增加基于siRNA的药物的安全性，同时保持基因沉默的效力。
Despite recent progress, systemic delivery remains the major hurdle for development of safe and effective small inhibitory RNA (siRNA)-based therapeutics. Encapsulation of siRNA into liposomes is a promising option to overcome obstacles such as low stability in serum and inefficient internalization by target cells. However, a major liability of liposomes is the potential to induce an acute inflammatory response, thereby increasing the risk of numerous adverse effects. In this study, we characterized a liposomal siRNA delivery vehicle, LNP201, which is capable of silencing an mRNA target in mouse liver by over 80%. The biodistribution profile, efficacy after single and multiple doses, mechanism of action, and inflammatory toxicity are characterized for LNP201. Furthermore, we demonstrate that the glucocorticoid receptor (GR) agonist dexamethasone (Dex) inhibits LNP201-induced cytokine release, inflammatory gene induction, and mitogen-activated protein kinase (MAPK) phosphorylation in multiple tissues. These data present a possible clinical strategy for increasing the safety profile of siRNA-based drugs while maintaining the potency of gene silencing.