Polyelectrolyte Complexes : Linking Chemistry and Structure to Biological Function

聚电解质复合物：将化学和结构与生物功能联系起来

• 批准号: 204990-2013
• 负责人: Buschmann, Michael
• 金额: $ 3.05万
• 依托单位: École Polytechnique de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=638067
• 关键词: Polyelectrolyte; Complexes; Linking; Chemistry; Structure

Polyelectrolyte complexes are nanoparticles that form via electrostatic attraction between a polycation and polyanion. A particular class of these systems is used to introduce genetic material into cells when the polyanion is a nucleic acid sequence like DNA or RNA. We have studied these delivery systems using the polycation chitosan, a natural polymer of glucosamine that is partly acetylated, and plasmid DNA to express genes when delivered to the nucleus. We have also developed nanoparticles containing siRNA which stop expression of the target gene. Certain mechanisms by which these systems function efficiently have been elucidated using a family of custom-produced chitosans and a battery of physicochemical and structural characterization methods of the polymers and resulting nanostructures, in addition to assessment of cell uptake, intracellular trafficking and transgene expression in several cell types. This proposal aims to further elucidate the fundamental mechanisms by which effective and non-toxic delivery of nucleic acids into cells can be achieved. The overall objective is to provide design principles and elucidate mechanisms of biological function for efficient and non-toxic chitosan/nucleic acid delivery vehicles for gene expression/knockdown, recombinant protein production and in vivo applications in animals and humans. A vast number of studies are performed worldwide on nanoparticle systems for the intracellular delivery of nucleic acids generating increased knowledge of their function and biological effects. Nonetheless many studies are descriptive with only a minority revealing basic mechanisms that can be used to identify further systems which can be effective and safe. This proposal aims to extend our recent work where basic principles relating chemical and structural properties of polyelectrolyte complexes to their ability to effectively deliver nucleic acids to intracellular sites of action will be advanced. The results will be significant for the fields of nanotechnology and cell biology.

聚电解质络合物是通过聚阳离子和聚阴离子之间的静电吸引而形成的纳米颗粒。当多阴离子是DNA或RNA之类的核酸序列时，这类特殊的系统被用来将遗传物质引入细胞。我们使用聚阳离子壳聚糖(一种部分乙酰化的氨基葡萄糖的天然聚合物)和质粒DNA研究了这些递送系统，当递送到细胞核时，表达基因。我们还开发了含有siRNA的纳米颗粒，可以阻止目标基因的表达。除了评估几种细胞类型的细胞摄取、细胞内运输和转基因表达外，这些系统有效发挥作用的某些机制已经通过一系列定制的壳聚糖和一系列聚合物及其纳米结构的物理化学和结构表征方法来阐明。这一提议旨在进一步阐明有效和无毒地将核酸输送到细胞内的基本机制。总体目标是提供高效无毒的壳聚糖/核酸输送载体的设计原理和生物学功能机制，用于基因表达/敲除、重组蛋白生产和在动物和人类体内的应用。世界各地对纳米粒子系统进行了大量的研究，以便在细胞内传递核酸，从而增加了对其功能和生物效应的了解。尽管如此，许多研究都是描述性的，只有一小部分揭示了可用于确定进一步有效和安全的系统的基本机制。这项提议旨在扩展我们最近的工作，在这些工作中，将提出将聚电解质复合体的化学和结构特性与其有效地将核酸输送到细胞内作用部位的能力相关的基本原理。这一结果将对纳米技术和细胞生物学领域具有重要意义。