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首页> 外文期刊>Molecular pharmaceutics >Delivery of siRNA Complexed with Palmitoylated alpha-Peptide/beta-Peptoid Cell-Penetrating Peptidomimetics: Membrane Interaction and Structural Characterization of a Lipid-Based Nanocarrier System
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Delivery of siRNA Complexed with Palmitoylated alpha-Peptide/beta-Peptoid Cell-Penetrating Peptidomimetics: Membrane Interaction and Structural Characterization of a Lipid-Based Nanocarrier System

机译：交付的siRNA与棕榈酰化的α-肽/β-类肽穿透肽模拟物复合：膜相互作用和基于脂质的纳米载体系统的结构表征。

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摘要

Proteolytically stable alpha-peptide/beta-peptoid peptidomimetics constitute promising cell-penetrating carrier candidates exhibiting superior cellular uptake as compared to commonly used cell-penetrating peptides (CPPs). The aim of the present study was to explore the potential of these peptidomimetics for delivery of small interfering RNA (siRNA) to the cytosol by incorporation of a palmitoylated peptidomimetic construct into a cationic lipid-based nanocarrier system. The optimal construct was selected on the basis of the effect of palmitoylation and the influence of the length of the peptidomimetic on the interaction with model membranes and the cellular uptake. Palmitoylation enhanced the peptidomimetic adsorption to supported lipid bilayers as studied by ellipsometry. However, both palmitoylation and increased peptidomimetic chain length were found to be beneficial in the cellular uptake studies using fluorophore-labeled analogues. Thus, the longer palmitoylated peptidomimetic was chosen for further formulation of siRNA in a dioleoylphosphatidylethanolamine/cholesteryl hemisuccinate (DOPE/CHEMS) nanocarrier system, and the resulting nanoparticles were found to mediate efficient gene silencing in vitro. Cryo-transmission electron microscopy (cryo-TEM) revealed multilamellar, onion-like spherical vesicles, and small-angle X-ray scattering (SAXS) analysis confirmed that the majority of the lipids in the nanocarriers were organized in lamellar structures, yet coexisted with a hexagonal phase, which is important for efficient nanocarrier-mediated endosomal escape of siRNA ensuring cytosolic delivery. The present work is a proof-of-concept for the use of alpha-peptides/beta-peptoid peptidomimetics in an efficient delivery system that may be more generally exploited for the intracellular delivery of biomacromolecular drugs.
机译：蛋白水解稳定的α-肽/β-拟肽模拟物构成了有希望的穿透细胞的载体候选物，与常用的穿透细胞的肽（CPPs）相比，它们表现出优异的细胞吸收能力。本研究的目的是通过将棕榈酰化的拟肽构建体掺入基于阳离子脂质的纳米载体系统中，探索这些拟肽将小干扰RNA（siRNA）传递至细胞质的潜力。根据棕榈酰化作用的影响以及拟肽的长度对与模型膜相互作用和细胞摄取的影响，选择最佳构建体。通过椭圆偏振法研究，棕榈酰化增强了拟肽对支持的脂质双层的吸附。然而，在使用荧光团标记的类似物进行细胞摄取研究中，棕榈酰化和增加的拟肽链长度均被发现是有益的。因此，选择更长的棕榈酰化拟肽用于在油酰磷脂酰乙醇胺/胆固醇半琥珀酸酯（DOPE / CHEMS）纳米载体系统中进一步配制siRNA，并且发现所得的纳米颗粒可在体外介导有效的基因沉默。低温透射电镜（cryo-TEM）显示多层的洋葱状球形囊泡，小角X射线散射（SAXS）分析证实，纳米载体中的大多数脂质均以层状结构组织，但与六角相，对于有效的纳米载体介导的siRNA内体逃逸（确保胞质递送）非常重要。目前的工作是在有效传递系统中使用α肽/β拟肽拟肽的概念验证，该系统可能更普遍地用于生物大分子药物的细胞内传递。

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