Development of Sulfonium- and Phosphonium-based Cationic Lipid Materials for mRNA Delivery

摘要 基于信使核糖核酸的治疗在疾病预防和治疗中具有广泛的应用 治疗。然而，它的广泛实际应用在很大程度上受到交付的限制。 担忧。阳离子脂类是信使核糖核酸传递的有效载体材料 脂类分子的化学结构是决定给药效果的关键。 然而，目前还没有被广泛接受的合理脂肪的指导原则。 分子结构设计以达到假定的生物效应。整合了 组合化学和体外/体内筛选方法已被证明 有助于开发有效的脂质载体。在合成上投入了很大的努力。 具有新的化学结构的新脂类。然而，尽管有这些令人振奋的结果， 目前开发的几乎所有用于mRNA递送的阳离子脂类都含有初级， 仲基、叔基或季胺基团作为带电单元与之相互作用 货运核糖核酸。在这项研究中，我们建议开发两种新型的阳离子脂质 含硫、膦分子的头部和可生物降解的尾部 并探讨它们在体外信使核糖核酸传递中的应用。我们的假设是相反的 对于传统的胺基阳离子脂类，硫基和膦基脂类 将具有前所未有的自组装行为，信使核糖核酸的传递性能，细胞 靶向和生物兼容性特征。通过使用组合库合成策略， 在体外筛选方法和处方优化方法上，本项目属首例 开发可生物降解的硫膦基脂类，并探索其 细胞内信使核糖核酸传递的可行性和安全性新开发的类脂材料 这项研究还可以用于未来的研究，以提供其他类型的治疗方法， 例如小分子药物、蛋白质和基因。

SUMMARY The mRNA-based therapeutics has wide applications in disease prevention and treatment. However, its wide practical application is largely limited by the delivery concerns. Cationic lipids are effective carrier materials for mRNA delivery and the chemical structure of lipid molecules is critical in determining the delivery efficacy. However, currently, there are no wide-accepted guiding principles exist for rational lipid molecule structure design to achieve presumed biological effects. The integration of combinatorial chemistry and in vitro/in vivo screening approach has been demonstrated useful in developing effective lipid carriers. Great efforts have been put into the synthesis of new lipids with novel chemical structures. However, despite all the promising results, almost all currently developed cationic lipids for mRNA delivery contain primary, secondary, tertiary, or quaternized amino groups as the chargeable units to interact with the cargo mRNAs. In this study, we propose to develop two new types of cationic lipid molecules with sulfonium- and phosphonium-containing heads and biodegradable tails and explore their applications in in vitro mRNA delivery. Our hypothesis is that contrary to traditional amine-based cationic lipids, the sulfonium- and phosphonium-based lipids will have unprecedented self-assembly behaviors, mRNA delivery performances, cell targeting, and biocompatibility profiles. By using combinatorial library synthesis strategy, in vitro screening approach, and formulation optimization methods, this project is the first to develop biodegradable sulfonium- and phosphonium-based lipids and to explore their feasibility and safety for intracellular mRNA delivery. The new lipid materials developed in this study can also be used in future studies to deliver other types of therapeutics, such as small molecule drugs, proteins, and genes.