Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan,
Int J Nanomedicine. 2018 Dec 10;13:8395-8410. doi: 10.2147/IJN.S188016. eCollection 2018.
The development of targeted drug delivery systems is a rapidly growing area in the field of nanomedicine.
We report herein on optimizing the targeting efficiency of a lipid nanoparticle (LNP) by manipulating the acid dissociation constant () value of its membrane, which reflects its ionization status. Instead of changing the chemical structure of the lipids to achieve this, we used a mixture of two types of pH-sensitive cationic lipids that show different values in a single LNP. We mixed various ratios of YSK05 and YSK12-C4 lipids, which have values of 6.50 and 8.00, respectively, in one formulation (referred to as YSK05/12-LNP).
The of the YSK05/12-LNP was dependent not only on the molar ratio of each lipid but also on the individual contribution of each lipid to the final (the YSK12-C4 lipid showed a higher contribution). Furthermore, we succeeded in targeting and delivering short interfering RNA to liver sinusoidal endothelial cells using one of the YSK05/12-LNPs which showed an optimum value of 7.15 and an appropriate ionization status (~36% cationic charge) to permit the particles to be taken up by liver sinusoidal endothelial cells.
This strategy has the potential for preparing custom LNPs with endless varieties of structures and final values, and would have poten tial applications in drug delivery and ionic-based tissue targeting.
靶向药物传递系统的发展是纳米医学领域中一个快速发展的领域。
我们在此报告通过操纵其膜的酸离解常数（pKa）值来优化脂质纳米颗粒（LNP）的靶向效率，该值反映了其电离状态。我们没有通过改变脂质的化学结构来实现这一点，而是使用两种类型的 pH 敏感阳离子脂质的混合物，在单个 LNP 中显示出不同的 pKa 值。我们混合了各种比例的 YSK05 和 YSK12-C4 脂质，它们在一个配方中的 pKa 值分别为 6.50 和 8.00（称为 YSK05/12-LNP）。
YSK05/12-LNP 的 pKa 值不仅取决于每种脂质的摩尔比，还取决于每种脂质对最终 pKa 值的单独贡献（YSK12-C4 脂质的贡献更高）。此外，我们成功地使用 YSK05/12-LNP 之一将短干扰 RNA 靶向并递送至肝窦内皮细胞，该 LNP 具有最佳的 pKa 值 7.15 和适当的电离状态（~36%的正电荷），允许颗粒被肝窦内皮细胞摄取。
这种策略有可能制备具有各种结构和最终 pKa 值的定制 LNP，并有可能在药物传递和基于离子的组织靶向方面得到应用。
