Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract.
Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract.
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DOI：
10.1038/s41598-018-20632-6
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发表时间：
2018-02-01
影响因子：
4.6
通讯作者：
Whitehead KA
中科院分区：
文献类型：
--
作者：
Ball RL;Bajaj P;Whitehead KA
口服给药是一种患者友好的给药方式，是局部肠道治疗的首选给药方式。此前已被证明可将siRNA运送到肠道上皮细胞的类脂纳米粒，具有治疗肠道疾病的潜力。然而，目前还不清楚这些颗粒是否有可能口服。为了更好地了解脂质纳米粒在胃肠道(GI)中的命运，我们研究了在体外胃和肠道条件下的递送。脂质纳米粒在暴露在pH值低至1.2的溶液中后仍然有效和稳定。在“喂食”而不是“禁食”胃酶和胆盐的浓度下，疗效会降低。粘蛋白的存在也降低了Caco-2细胞的效力，尽管这种影响通过增加脂质纳米颗粒中聚乙二醇酯的百分比而略有缓解。小鼠的生物分布研究表明，携带小干扰RNA的纳米颗粒在胃肠道中至少保留了8 小时。虽然在口服LNP后最初没有观察到基因沉默，但共聚焦显微镜证实纳米颗粒进入了小鼠小肠和结肠的上皮细胞。综上所述，这些数据表明，口服的LNPs应该在胃和上肠受到保护，以促进siRNA输送到肠道上皮细胞。
Oral delivery, a patient-friendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Lipidoid nanoparticles, which have been previously shown to deliver siRNA to intestinal epithelial cells, have potential to treat intestinal disease. It is unknown, however, whether the oral delivery of these particles is possible. To better understand the fate of lipid nanoparticles in the gastrointestinal (GI) tract, we studied delivery under deconstructed stomach and intestinal conditions in vitro. Lipid nanoparticles remained potent and stable following exposure to solutions with pH values as low as 1.2. Efficacy decreased following exposure to “fed”, but not “fasting” concentrations of pepsin and bile salts. The presence of mucin on Caco-2 cells also reduced potency, although this effect was mitigated slightly by increasing the percentage of PEG in the lipid nanoparticle. Mouse biodistribution studies indicated that siRNA-loaded nanoparticles were retained in the GI tract for at least 8 hours. Although gene silencing was not initially observed following oral LNP delivery, confocal microscopy confirmed that nanoparticles entered the epithelial cells of the mouse small intestine and colon. Together, these data suggest that orally-delivered LNPs should be protected in the stomach and upper intestine to promote siRNA delivery to intestinal epithelial cells.
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影响因子：
3.7
作者：
Kalantzi, L;Goumas, K;Reppas, C
通讯作者：
Reppas, C
DOI：
10.1038/mtna.2013.2
发表时间：
2013-03-05
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.1
作者：
Ensign, Laura M.;Cone, Richard;Hanes, Justin
通讯作者：
Hanes, Justin
DOI：
10.1046/j.1365-2036.1996.55197000.x
发表时间：
1996-10-01
影响因子：
7.6
作者：
Gan, KH;Geus, WP;Heijerman, HGM
通讯作者：
Heijerman, HGM
达到脂质纳米颗粒的长期稳定性：检查pH，温度和冻干的影响。
影响因子：
8
作者：
Ball RL;Bajaj P;Whitehead KA
通讯作者：
Whitehead KA