In vitro-in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery.
In vitro-in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery.
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DOI：
10.1021/nn301922x
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发表时间：
2012-08-28
期刊：
影响因子：
17.1
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
--
作者：
Whitehead, Kathryn A.;Matthews, Jonathan;Chang, Philip H.;Niroui, Farnaz;Dorkin, J. Robert;Severgnini, Mariano;Anderson, Daniel G.
临床上可行的siRNA递送系统的开发中的一个重大挑战是缺乏体外-体内可翻译性：许多最初在细胞培养中有希望的递送载体在动物中不保留功效。尽管其重要性，但关于体外方法学的预测性质的信息很少，最有可能是由于与生成体外-体内数据集相关的成本和时间。最近，已经开发了高通量技术，其允许在多个实验系统中检查数百种脂质纳米颗粒制剂的转染效率。由此产生的大数据集允许开发肝细胞递送载体的体外和表征数据与体内功效之间的相关性。一致性的配方技术和用于体外实验的细胞类型被发现显着影响相关性，与原代肝细胞和HeLa细胞产生最预测的数据。有趣的是，使用HeLa细胞获得的体外数据比小鼠肝癌Hepa 1 -6细胞更能预测体内性能。在表征参数中，仅siRNA包埋效率部分预测体内沉默潜力，而ζ电位和令人惊讶的通过动态光散射测量的纳米颗粒尺寸（当< 300 nm时）不是。这些数据为临床上可行的siRNA递送材料的开发提供了指导原则，并有可能降低实验成本，同时改善材料在动物中的翻译。
A significant challenge in the development of clinically-viable siRNA delivery systems is a lack of in vitro – in vivo translatability: many delivery vehicles that are initially promising in cell culture do not retain efficacy in animals. Despite its importance, little information exists on the predictive nature of in vitro methodologies, most likely due to the cost and time associated with generating in vitro – in vivo data sets. Recently, high-throughput techniques have been developed that have allowed the examination of hundreds of lipid nanoparticle formulations for transfection efficiency in multiple experimental systems. The large resulting data set has allowed the development of correlations between in vitro and characterization data and in vivo efficacy for hepatocellular delivery vehicles. Consistency of formulation technique and the type of cell used for in vitro experiments was found to significantly affect correlations, with primary hepatocytes and HeLa cells yielding the most predictive data. Interestingly, in vitro data acquired using HeLa cells was more predictive of in vivo performance than mouse hepatoma Hepa1-6 cells. Of the characterization parameters, only siRNA entrapment efficiency was partially predictive of in vivo silencing potential, while zeta potential and, surprisingly, nanoparticle size (when < 300 nm) as measured by dynamic light scattering were not. These data provide guiding principles in the development of clinically-viable siRNA delivery materials and have the potential to reduce experimental costs while improving the translation of materials into animals.
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