Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery
Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery
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DOI：
10.1073/pnas.1306529110
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发表时间：
2013-08-06
影响因子：
11.1
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Alabi, Christopher A.;Love, Kevin T.;Anderson, Daniel G.
纳米颗粒介导的siRNA递送是一个复杂的过程，需要跨越许多细胞外和细胞内屏障进行转运。因此，开发用于有效递送的纳米颗粒将受益于理解与这些屏障相关的参数如何与纳米颗粒的物理化学性质相关。在这里，我们使用多参数的方法来评估脂质纳米颗粒（LNP），以确定结构，生物功能和生物活性之间的关系。我们的研究结果表明，对与递送障碍相关的多个参数（例如SiRNA包埋、pK（a）、LNP稳定性和细胞摄取）的整体评估可以作为LNP在体内发展的有用预筛选工具。这种多参数方法补充了单独使用体外疗效结果进行预筛选，并通过最大限度地减少假阴性来改善体外-体内转化。对于本工作中使用的LNP，多个参数的评价使得能够将LNP pK（a）鉴定为体外和体内LNP功能和活性的关键决定因素之一。预计这种类型的分析可以帮助鉴定有意义的结构-功能-活性关系，改善体内使用前纳米颗粒的体外筛选过程，并促进未来有效纳米载体的设计。
Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK(a), LNP stability, and cell uptake as a collective may serve as a useful prescreening tool for the advancement of LNPs in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. For the LNPs used in this work, the evaluation of multiple parameters enabled the identification of LNP pK(a) as one of the key determinants of LNP function and activity both in vitro and in vivo. It is anticipated that this type of analysis can aid in the identification of meaningful structure-function-activity relationships, improve the in vitro screening process of nanoparticles before in vivo use, and facilitate the future design of potent nanocarriers.