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首页> 外文学位 >Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics.
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Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics.

机译：球形核酸作为基于核酸的治疗剂的细胞内剂。

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摘要

Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct novel SNA-based nanomaterials with desired properties and applying targeting moieties to the SNA platform to achieve cell type specific gene regulation effects. Due to the flexibility of the SNA approach, the SNA platform can potentially be applied to many genetic disorders through tailored target specificities.
机译：人类基因组和转录组的非编码序列的最新功能发现可能会导致革命性的治疗方式，因为非编码RNA（ncRNA）可以用作治疗病原基因的治疗剂。迄今为止，由于以有效的，细胞特异性的和无毒的方式递送寡核苷酸试剂的挑战，很少有基于核酸的治疗剂被转入临床。未修饰的寡核苷酸试剂会在生物液中被酶降解而被迅速破坏，并且在没有转染试剂的帮助下难以穿过质膜，而转染试剂通常会引起炎症，细胞毒性或免疫原性副作用。球形核酸（SNA）是由密集组织且高度定向的寡核苷酸组成的纳米粒子，为在反义和RNA干扰（RNAi）途径中规避这些问题提出了一种可能的解决方案。 SNA的独特三维结构可保护生物活性寡核苷酸免于递送过程中的非特异性降解，并通过脂质筏依赖性的小窝介导的途径支持其靶向A类清道夫受体和内吞作用。由于其独特的结构，SNA能够跨细胞膜并作为单个实体调节靶基因的表达，而不会触发细胞的先天免疫应答。在本文中，我的论文集中在理解SNA与细胞成分之间的相互作用以及开发基于SNA的纳米结构以提高治疗能力。具体来说，我开发了一种新型的基于SNA的纳米级试剂，用于递送治疗性寡核苷酸来操纵microRNA（miRNA）（内源转录后基因调节剂）。我通过全身注射研究了涉及miRNA的SNA在细胞和体内鼠类疾病模型中的抗癌或抗炎症反应中的作用。此外，我探索了使用不同的策略来构建具有所需特性的新型基于SNA的纳米材料，并将靶向部分应用于SNA平台以实现细胞类型特异性基因调控效果的方法。由于SNA方法的灵活性，SNA平台可以通过量身定制的靶标特异性应用于许多遗传性疾病。

著录项

  • 作者

    Hao, Liangliang.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Cellular biology.;Molecular biology.;Oncology.;Nanotechnology.;Nanoscience.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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