A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy
A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy
复制标题
一种靶向骨形成表面的递送系统，以促进基于 RNAi 的合成代谢疗法
DOI：
10.1038/nm.2617
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发表时间：
2012-02-01
期刊：
影响因子：
82.9
通讯作者：
Qin, Ling
中科院分区：
文献类型：
--
作者：
Zhang, Ge;Guo, Baosheng;Qin, Ling
与骨形成受损相关的代谢性骨骼疾病是一个主要的临床挑战。治疗这些缺陷的一种方法是通过小干扰RNA（siRNA）沉默骨形成抑制基因，这些基因位于骨形成表面周围的小生境中的成骨谱系细胞中。我们开发了一种靶向系统，该系统涉及基于二油酰三甲基铵丙烷（DOTAP）的阳离子脂质体，该脂质体连接到天冬氨酸、丝氨酸、丝氨酸（（AspSerSer）（6））的六个重复序列上，用于将siRNA特异性递送到骨形成表面。使用这个系统，我们封装成骨siRNA，目标酪蛋白激酶-2相互作用蛋白-1（由Plekho 1编码，也称为Plekho 1）。使用我们的系统在大鼠体内全身递送Plekho 1 siRNA导致成骨细胞中siRNA的选择性富集和Plekho 1的随后耗尽。生物成像分析进一步表明，这种方法显著促进了健康和骨质疏松大鼠的骨形成，增强了骨微结构，增加了骨量。这些结果表明（AspSerSer）（6）-脂质体作为基于RNA干扰的骨合成代谢治疗的有希望的靶向递送系统。
Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference- based bone anabolic therapy.