Development of amine protecting group chemistry for long chain nucleic acids

在过去的几年里，能够选择性地将目标治疗药物递送到所需的确切部位的“智能”药物或药物递送载体引起了人们的广泛研究兴趣。然而，由于缺乏有效的输送工具，真正的智能药物尚未上市。脂质体是一种经过广泛研究的候选药物，用于创建可销售的、有效的智能药物输送载体，它是由模仿天然细胞膜的自组装脂质组成的纳米颗粒。然而，传统上，脂质体一直受到尺寸控制不佳、载药量低、长期储存稳定性差以及向目标的递送效率低等问题的困扰。虽然其他研究人员已经找到了解决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，通过结合引导 DNA 和脂质形成单链 (ss)DNA 加合物，脂质体可以自组装为具有预定义的尺寸、载药量和储存弹性。因此，该方法成功的关键步骤是能够形成明确的脂质-ssDNA 加合物。然而，这本身就具有挑战性，因为天然 ssDNA 链中可能存在多达 100 个竞争性胺基（除了要修饰的末端胺基），需要对非末端胺基进行保护，而使用传统化学方法不太可能完成保护。为了克服这个问题，我们计划利用霍尔实验室在合成和定制修饰纳米级水凝胶（称为纳米凝胶）方面的丰富经验。我们建议纳米凝胶可以用作单链DNA上非目标胺的物理保护基团，空间阻断与非末端胺的反应，同时还避免昂贵且耗时的保护基化学。该项目的成功完成预计将在短期内推出商业产品，SP-Nanobiotech 可以将其出售给其他研究人员（使公司能够继续发展），并在真正智能药物输送工具的长期设计方面迈出关键一步，有可能显着改善健康结果。

"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.