Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments.
Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments.
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DOI：
10.3390/pharmaceutics12111042
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发表时间：
2020-10-30
期刊：
影响因子：
5.4
通讯作者：
Ghosh D
中科院分区：
文献类型：
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作者：
Zhang H;Leal J;Soto MR;Smyth HDC;Ghosh D
信使RNA是一类有前途的核酸治疗剂，用于治疗各种疾病，包括遗传疾病。稳定有效的mRNA肺部递送系统的开发将使肺部局部的高治疗浓度能够提高疗效并限制潜在的毒性。在这项研究中，我们采用了实验设计（DOE）策略来筛选脂质纳米颗粒组合物的库，以鉴定在雾化之前和之后都具有高效力的制剂。脂质纳米颗粒（LNP）在4 °C下储存至少14天显示出稳定的物理化学性质，并且大多数制剂表现出大于80%的高包封率。通常，在雾化时，LNP制剂显示出增加的粒度和降低的包封效率。增加聚乙二醇（PEG）-脂质的摩尔比显着降低大小，但也细胞内的蛋白质表达的mRNA。我们确定了四种即使在雾化后仍在体外具有更高细胞内蛋白表达能力的制剂，然后在体内研究中对其进行评估。结果发现，荧光素酶蛋白主要在雾化前后的四个铅制剂的小鼠肺中表达。这项研究表明，LNP有望应用于雾化介导的肺mRNA递送。
Messenger RNA is a class of promising nucleic acid therapeutics to treat a variety of diseases, including genetic diseases. The development of a stable and efficacious mRNA pulmonary delivery system would enable high therapeutic concentrations locally in the lungs to improve efficacy and limit potential toxicities. In this study, we employed a Design of Experiments (DOE) strategy to screen a library of lipid nanoparticle compositions to identify formulations possessing high potency both before and after aerosolization. Lipid nanoparticles (LNPs) showed stable physicochemical properties for at least 14 days of storage at 4 °C, and most formulations exhibited high encapsulation efficiencies greater than 80%. Generally, upon nebulization, LNP formulations showed increased particle size and decreased encapsulation efficiencies. An increasing molar ratio of poly-(ethylene) glycol (PEG)-lipid significantly decreased size but also intracellular protein expression of mRNA. We identified four formulations possessing higher intracellular protein expression ability in vitro even after aerosolization which were then assessed in in vivo studies. It was found that luciferase protein was predominately expressed in the mouse lung for the four lead formulations before and after nebulization. This study demonstrated that LNPs hold promise to be applied for aerosolization-mediated pulmonary mRNA delivery.
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影响因子：
10.8
作者：
Kauffman, Kevin J.;Dorkin, J. Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
12.4
作者：
Akinc, Akin;Goldberg, Michael;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
16.6
作者：
Jayaraman, Muthusamy;Ansell, Steven M.;Mui, Barbara L.;Tam, Ying K.;Chen, Jianxin;Du, Xinyao;Butler, David;Eltepu, Laxman;Matsuda, Shigeo;Narayanannair, Jayaprakash K.;Rajeev, Kallanthottathil G.;Hafez, Ismail M.;Akinc, Akin;Maier, Martin A.;Tracy, Mark A.;Cullis, Pieter R.;Madden, Thomas D.;Manoharan, Muthiah;Hope, Michael J.
通讯作者：
Hope, Michael J.
DOI：
10.1186/s40348-015-0022-6
发表时间：
2015-12
期刊：
Molecular and cellular pediatrics
影响因子：
--
作者：
Antony JS;Dewerth A;Haque A;Handgretinger R;Kormann MS
通讯作者：
Kormann MS
DOI：
10.1038/mtna.2012.28
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
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作者：
通讯作者：
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