Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom.
Acc Chem Res. 2012 Jul 17;45(7):1140-52. doi: 10.1021/ar200263c. Epub 2012 Mar 5.
Nucleic acids are the foundation stone of all cellular processes. Consequently, the use of DNA or RNA to treat genetic and acquired disorders (so called gene therapy) offers enormous potential benefits. The restitution of defective genes or the suppression of malignant genes could target a range of diseases, including cancers, inherited diseases (cystic fibrosis, muscular dystrophy, etc.), and viral infections. However, this strategy has a major barrier: the size and charge of nucleic acids largely restricts their transit into eukaryotic cells. Potential strategies to solve this problem include the use of a variety of natural and synthetic nucleic acid carriers. Driven by the aim and ambition of translating this promising therapeutic approach into the clinic, researchers have been actively developing advanced delivery systems for nucleic acids for more than 20 years. A decade ago we began our investigations of solid-phase techniques to construct families of novel nucleic acid carriers for transfection. We envisaged that the solid-phase synthesis of polycationic dendrimers and derivatized polyamimes would offer distinct advantages over solution phase techniques. Notably in solid phase synthesis we could take advantage of mass action and streamlined purification procedures, while simplifying the handling of compounds with high polarities and plurality of functional groups. Parallel synthesis methods would also allow rapid access to libraries of compounds with improved purities and yields over comparable solution methodologies and facilitate the development of structure activity relationships. We also twisted the concept of the solid-phase support on its head: we devised miniaturized solid supports that provided an innovative cell delivery vehicle in their own right, carrying covalently conjugated cargos (biomolecules) into cells. In this Account, we summarize the main outcomes of this series of chemically related projects.
核酸是所有细胞过程的基石。因此，使用 DNA 或 RNA 来治疗遗传和获得性疾病（所谓的基因治疗）具有巨大的潜在益处。修复有缺陷的基因或抑制恶性基因可以针对一系列疾病，包括癌症、遗传病（囊性纤维化、肌肉营养不良症等）和病毒感染。然而，这种策略存在一个主要障碍：核酸的大小和电荷在很大程度上限制了它们进入真核细胞的转运。解决这个问题的潜在策略包括使用各种天然和合成的核酸载体。为了将这一有前途的治疗方法转化为临床应用，研究人员 20 多年来一直在积极开发核酸的先进传递系统。十年前，我们开始研究固相技术，以构建一系列新型核酸载体进行转染。我们设想，聚阳离子树状大分子和衍生聚酰胺的固相合成将比溶液相技术具有明显的优势。特别是在固相合成中，我们可以利用质量作用定律和简化的纯化程序，同时简化处理高极性和多功能团化合物的操作。平行合成方法还可以快速获得具有更高纯度和收率的化合物库，优于类似的溶液方法，并有助于开发结构-活性关系。我们还颠覆了固相支持的概念：我们设计了小型化的固相支持物，它们本身就提供了一种创新的细胞传递载体，将共价连接的载体（生物分子）带入细胞。在本账目中，我们总结了这一系列化学相关项目的主要成果。
