Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles
Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles
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DOI：
10.1016/j.actbio.2019.11.022
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发表时间：
2020-01-15
影响因子：
9.7
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
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作者：
Sato, Yusuke;Okabe, Nana;Harashima, Hideyoshi
尽管小尺寸脂质纳米粒(LNPs)对于改善组织渗透和高效给药非常重要，但它们较差的稳定性和细胞内的转运显著阻碍了它们作为有效的小尺寸LNPs的应用。据报道，脂类成分在LNPs中的扩散和蛋白质在LNPs表面的吸附都是导致LNPs活性降低的原因。为了解决这个问题，我们重点研究了不同长度和形状的pH敏感阳离子脂类疏水支架的化学结构。由pH敏感的阳离子脂质与长的线性支架组成的LNPs以剂量依赖的方式诱导基因沉默，而具有经典支架长度(C18)的LNPs则失败。将辅助脂质从胆固醇替换为卵鞘磷脂(ESM)，可以形成直径约为22 nm的较小LNPs，并增强基因沉默活性。大多数ESM位于外层，起到稳定LNPs的作用。长的线性支架有助于与包括ESM在内的含磷胆碱的脂类不相容。这一贡献依赖于对pH敏感的阳离子脂类的支架长度。虽然含有磷胆碱的脂类通常抑制膜融合介导的内体逃逸，但长而线性的支架有助于避免抑制作用并增强LNPs的效力。这些发现为合理设计pH敏感的阳离子脂质结构和选择合适的辅助脂类提供了有用的信息，并将促进高效小尺寸LNPs的开发。尽管小尺寸脂质纳米粒(LNPs)对于改善组织渗透和有效的药物输送非常重要，但与尺寸减小相关的稳定性和细胞内转运的下降显著阻碍了高效小尺寸LNPs的开发。我们对效力降低的机制的有限理解也阻碍了更有效的小型LNPs的发展。本研究的结果表明，由pH敏感的阳离子脂类组成的长线性疏水支架可以克服核酸输送效率的损失。此外，长长的疏水支架导致了与中性磷脂的不相容，从而导致了有效的内质粒逃逸。这些发现为合理设计pH敏感的阳离子脂类结构提供了有用的信息，并将促进高效小尺寸LNPs的开发。(C)2019年Acta Materialia Inc.由Elsevier Ltd.出版。
Despite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, their poor stability and intracellular trafficking significantly hinders their use as potent small-sized LNPs. It has been reported that both the diffusion of lipid components from LNPs and the adsorption of proteins on the surface of LNPs are responsible for their decreased potency. To overcome this issue, we focused on the chemical structure of hydrophobic scaffolds of pH-sensitive cationic lipids with various lengths and shapes. LNPs composed of a pH-sensitive cationic lipid with long, linear scaffolds induced gene silencing in a dose-dependent manner, while LNPs with a classical scaffold length (C18) failed. Replacing the helper lipid from cholesterol to egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of similar to 22 nm and enhanced gene silencing activity. Most of the ESMs were located in the outer layer and functioned to stabilize the LNPs. Long, linear scaffolds contributed to immiscibility with phosphocholine-containing lipids including ESM. This contribution was dependent on the scaffold length of pH-sensitive cationic lipids. Although phosphocholine-containing lipids usually inhibit membrane fusion-mediated endosomal escape, long, linear scaffolds contributed to avoiding the inhibitory effect and to enhance the potency of the LNPs. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and the selection of appropriate helper lipids and will facilitate the development of highly potent small-sized LNPs.Statement of significanceDespite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, the size reduction-associated decrease in the stability and intracellular trafficking significantly hinders the development of potent small-sized LNPs. Our limited understanding of the mechanism underlying the reduced potency has also hindered the development of more potent small-sized LNPs. The findings of the present study indicate that long and linear hydrophobic scaffolds of pH-sensitive cationic lipids could overcome the loss of efficiency for nucleic acid delivery. In addition, the long hydrophobic scaffolds led to immiscibility with neutral phospholipids, resulting in efficient endosomal escape. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and will facilitate the development of highly potent small-sized LNPs. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd.