Development of amine protecting group chemistry for long chain nucleic acids

在过去的几年里，能够选择性地将靶向治疗药物输送到所需位置的“智能”药物或药物输送工具吸引了人们极大的研究兴趣。然而，由于缺乏可用的高效递送工具，还没有真正智能的药物进入市场。一个被广泛研究的创造市场上有效的智能药物输送载体的候选是脂质体，这是一种由模仿天然细胞膜的自组装脂类组成的纳米颗粒。然而，脂质体传统上一直受到尺寸控制差、载药量低、长期储存稳定性差以及靶向递送效率低的困扰(S)。虽然其他研究人员已经为这些问题找到了巧妙但互不相容的解决方案，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。利用DNA作为组织支架，通过将DNA和脂类结合成单链DNA加合物，脂质体可以自组装成具有预定大小、载药量和储存弹性的药物。因此，这种方法成功的关键一步是能够形成定义明确的脂质-单链DNA加合物。然而，这本身就具有挑战性，因为天然单链DNA链中可能存在多达100个相互竞争的胺基团(除了目标修饰的末端胺基团)，需要保护非末端胺基团，这不太可能使用传统化学来完成。为了解决这个问题，我们计划利用霍尔实验室在合成和量身定制的纳米尺度水凝胶(称为纳米凝胶)方面的丰富经验。我们认为，纳米凝胶可以作为单链DNA上非靶标胺的物理保护基团，在空间上阻断与非端胺的反应，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带来SP-Nanobiotech可以出售给其他研究人员的商业产品(使公司继续增长)，并向真正智能药物输送车辆的长期设计迈出关键一步，有可能显著改善健康结果。

"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.