Development of Lipidoid-siRNA Formulations for Systemic Delivery to the Liver
Development of Lipidoid-siRNA Formulations for Systemic Delivery to the Liver
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DOI：
10.1038/mt.2009.36
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发表时间：
2009-05-01
影响因子：
12.4
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Akinc, Akin;Goldberg, Michael;Anderson, Daniel G.
RNA干扰疗法提供了特异性沉默靶基因表达的潜力，从而阻断致病蛋白的产生。开发安全有效的系统性小干扰RNA （siRNA）递送系统对siRNA的治疗应用至关重要。脂质和类脂质材料是目前研究最充分的siRNA肝脏递送系统，已在几种动物模型中使用，包括非人灵长类动物。在这里，我们描述了一种基于新型脂质样材料98N(12)-5(1)的多组分系统性siRNA递送系统的发展。我们发现，体内给药效果受到许多参数的影响，包括配方组成、颗粒聚乙二醇化的性质、药物负载程度以及颗粒大小等生物物理参数。特别是，聚乙二醇(PEG) -脂质锚链长度的微小变化会对体内疗效产生显著影响。开发的先导制剂是针对肝脏的（> 90%的注射剂量分配到肝脏），并且可以诱导完全可逆的，长时间的基因沉默，而不会失去活性-重复给药。
RNA interference therapeutics afford the potential to silence target gene expression specifically, thereby blocking production of disease-causing proteins. The development of safe and effective systemic small interfering RNA (siRNA) delivery systems is of central importance to the therapeutic application of siRNA. Lipid and lipid-like materials are currently the most well-studied siRNA delivery systems for liver delivery, having been utilized in several animal models, including nonhuman primates. Here, we describe the development of a multicomponent, systemic siRNA delivery system, based on the novel lipid-like material 98N(12)-5(1). We show that in vivo delivery efficacy is affected by many parameters, including the formulation composition, nature of particle PEGylation, degree of drug loading, and biophysical - parameters such as particle size. In particular, small changes in the anchor chain length of poly(ethylene glycol) (PEG) - lipids can result in significant effects on in vivo efficacy. The lead formulation developed is liver targeted (> 90% injected dose distributes to liver) and can induce fully reversible, long-duration gene silencing without loss of activity - following repeat administration.