Peptide Spiders: Peptide-Polymer Conjugates to Traffic Nucleic Acids.,Molecular Pharmaceutics

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Peptide Spiders: Peptide-Polymer Conjugates to Traffic Nucleic Acids.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-07-27 , DOI: 10.1021/acs.molpharmaceut.0c00714
Ester J Kwon ₁ , Henry Ko ₁ , Sangeeta N Bhatia _{2,

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Affiliation

Therapeutic nucleic acids hold great promise for the treatment of genetic diseases, yet the delivery of this highly charged macromolecular drug remains a challenge in the field. Peptides are promising agents to mediate nucleic acid delivery because they can encode a biological function to overcome the trafficking barriers. Electrostatic nanocomplexes of nucleic acid and peptides can achieve effective delivery, but the balance between their stability and biological function must be finely tuned. In this work, we explore two peptide building blocks that have been studied in the literature: targeting ligands and intracellular trafficking peptides. We grafted these peptides on a polyethylene glycol (PEG) backbone with eight sites for substitution to create so-called “peptide spiders”. These conjugates achieve stability via the well-known hydrophilic shielding effect of PEG. In addition, the coordination of peptide building blocks into multimers may create new biological properties, such as the well-known phenomena of increased binding avidity with multivalent ligands. In this work, we linked two trafficking peptides to the PEG backbone using either nonreducible or reducible chemistries and investigated the ability of these materials to carry silencing RNAs into mammalian cells. We then investigated these nanomaterials for their pharmacokinetic properties and silencing of undruggable targets in a mouse model of cancer. While reducible linkages were more potent at silencing in vitro, this effect was reversed when applied in the context of living animals. This work offers an insight into peptide-based delivery materials and investigates peptide–polymer linkages.

中文翻译：

肽蜘蛛：与交通核酸结合的肽-聚合物偶联物。

治疗性核酸在治疗遗传疾病方面具有很大的前景，但这种高电荷大分子药物的递送仍然是该领域的挑战。肽是有前途的介导核酸递送的试剂，因为它们可以编码生物学功能以克服运输障碍。核酸和多肽的静电纳米复合物可以实现有效的递送，但其稳定性和生物功能之间的平衡必须进行微调。在这项工作中，我们探索了文献中研究过的两种肽构建块：靶向配体和细胞内运输肽。我们将这些肽移植到具有八个取代位点的聚乙二醇 (PEG) 主链上，以创建所谓的“肽蜘蛛”。这些缀合物通过众所周知的 PEG 亲水屏蔽效应实现稳定性。此外，肽结构单元与多聚体的配位可能会产生新的生物学特性，例如众所周知的与多价配体结合亲合力增加的现象。在这项工作中，我们使用不可还原或可还原的化学物质将两种运输肽连接到 PEG 主链，并研究了这些材料将沉默的 RNA 携带到哺乳动物细胞中的能力。然后，我们在癌症小鼠模型中研究了这些纳米材料的药代动力学特性和不可药物靶标的沉默。虽然可还原的联系在体外沉默中更有效，但当应用于活体动物时，这种效果会被逆转。

更新日期：2020-09-09

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