Mucus-penetrating phage-displayed peptides for improved transport across a mucus-like model.
Mucus-penetrating phage-displayed peptides for improved transport across a mucus-like model.
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DOI：
10.1016/j.ijpharm.2018.09.055
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发表时间：
2018-12-20
影响因子：
5.8
通讯作者：
Ghosh D
中科院分区：
文献类型：
--
作者：
Leal J;Dong T;Taylor A;Siegrist E;Gao F;Smyth HDC;Ghosh D
这项工作的目的是使用噬菌体展示库作为筛选工具，以确定肽，促进运输通过粘液屏障。粘液是对颗粒和分子的复杂选择性屏障，限制渗透到粘膜组织的上皮表面。在粘液相关疾病如囊性纤维化（CF）中，与健康组织相比，粘液具有增加的粘弹性和更高浓度的共价和非共价物理缠结，这极大地阻碍了药物和颗粒穿过粘膜的渗透性和运输以用于治疗递送。CF肺部疾病和相关感染的治疗必须克服这种异常的粘膜屏障。阻碍有效药物渗透的关键瓶颈仍然存在，虽然最近的研究表明亲水性净中性电荷聚合物可以改善纳米颗粒的运输并最大限度地减少与粘液的相互作用，但缺乏可用的替代载体。我们假设针对CF粘液模型筛选噬菌体肽文库将导致鉴定能够改善粘液中转运的噬菌体展示肽序列。这些组合文库具有大量基于肽的制剂（108 - 109）的多样性，以实现对潜在的粘液穿透肽的前所未有的筛选。在此，展示发现的肽的噬菌体克隆显示在CF粘液模型中具有高达2.6倍的增强的扩散性。此外，我们证明与野生型对照相比，粘蛋白的结合亲和力降低。这些发现表明噬菌体展示文库可以用作改善经粘膜递送的策略。
The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108 - 109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery.
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影响因子：
11.1
作者：
Boucher, R. C.
通讯作者：
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