Development of amine protecting group chemistry for long chain nucleic acids

长链核酸胺保护基化学的发展

• 批准号: 477055-2014
• 负责人: Hoare, Todd
• 金额: $ 1.82万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=565598
• 关键词: Development; amine; protecting; group; chemistry

"Smart" drugs or drug delivery vehicles that can selectively deliver a target therapeutic to the exact site desired have attracted significant research interest over the last several years. However, no truly smart drug has yet to come to market due to a lack of available efficient delivery vehicles. One widely-investigated candidate for the creation of marketable, effective smart drug delivery vehicles are liposomes, nanoparticles comprised of self-assembled lipids that mimic natural cell membranes. However, liposomes have traditionally been plagued by poor control over size, low drug loading, poor long-term storage stability, and low delivery efficiency to their target(s). While other researchers have identified ingenious but incompatible solutions to these problems, our partner SP-Nanobiotech is the first to use DNA nanotechnology to overcome these challenges. Using DNA as an organizing scaffold, liposomes can be self-assembled with a pre-defined size, drug loading, and storage resilience using a combination of the directing DNA and lipid to single stranded (ss)DNA adducts. The key step to the success of this method is thus being able to form well-defined lipid-ssDNA adducts. This is, however, inherently challenging since as many as 100 competing amine groups may be present (aside from the terminal amine group targeted for modification) in the native ssDNA chains, requiring protection of the non-terminal amine groups that is unlikely to go to completion using conventional chemistries. To overcome this problem, we plan to leverage the Hoare lab's extensive experience in the synthesis and tailored modification of nanoscaled hydrogels called nanogels. We propose that nanogels can be used as physical protecting groups for the non-target amines on ssDNA, sterically blocking reactions with non-terminal amines while also avoiding costly and time-consuming protecting group chemistry. Successful completion of this project is expected to lead to a commercial product in the shorter term that SP-Nanobiotech could sell to other researchers (allowing the company to continue its growth) as well as take a key step forward to the longer-term design of truly smart drug delivery vehicles with the potential to significantly improve health outcomes.

在过去几年中，可以选择性地将靶向治疗剂递送到所需的确切部位的“智能”药物或药物递送载体吸引了显著的研究兴趣。然而，由于缺乏有效的运载工具，真正的智能药物尚未上市。一个被广泛研究的用于创造可销售的、有效的智能药物递送载体的候选者是脂质体，由模仿天然细胞膜的自组装脂质组成的纳米颗粒。然而，脂质体传统上受到尺寸控制差、载药量低、长期储存稳定性差和对其靶标的递送效率低的困扰。虽然其他研究人员已经确定了这些问题的巧妙但不兼容的解决方案，但我们的合作伙伴SP-Nanobiotech是第一个使用DNA纳米技术来克服这些挑战的公司。使用DNA作为组织支架，脂质体可以使用将DNA和脂质引导至单链（ss）DNA加合物的组合自组装成具有预定大小、载药量和储存弹性。因此，这种方法成功的关键步骤是能够形成定义明确的脂质-ssDNA加合物。然而，这是固有的挑战，因为天然ssDNA链中可能存在多达100个竞争性胺基（除了靶向修饰的末端胺基），需要保护非末端胺基，这不太可能使用常规化学方法完成。为了克服这个问题，我们计划利用Hoare实验室在纳米级水凝胶（称为纳米凝胶）的合成和定制改性方面的丰富经验。我们建议纳米凝胶可以用作ssDNA上非目标胺的物理保护基团，在空间上阻断与非末端胺的反应，同时也避免了昂贵和耗时的保护基团化学。该项目的成功完成预计将在短期内导致SP-Nanobiotech可以出售给其他研究人员的商业产品（允许公司继续增长），并朝着真正智能药物输送车辆的长期设计迈出关键一步，有可能显着改善健康结果。