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

用于 mRNA 递送的锍基和鏻基阳离子脂质材料的开发

• 批准号: 10621165
• 负责人: Yamin Li
• 金额: $ 8.15万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621165
• 关键词: Amines; Behavior; Biological; Biological Assay; Bioluminescence; CRISPR/Cas technology; Cells; Charge; Chemical Structure; Chemicals; Chemistry; Clinical Trials; Development; Drug Delivery Systems; Emergency Situation; Encapsulated; Evaluation; Flow Cytometry; Fluorescence Microscopy; Formulation; Future; Genes; Goals; Head; Hydrophobicity; In Vitro; Investigation; Libraries; Lipids; Mammalian Cell; Mediating; Messenger RNA; Methods; Morphology; Performance; Pharmaceutical Preparations; Play; Positioning Attribute; Property; Proteins; RNA vaccine; Role; Scheme; Structure; System; Tail; Therapeutic; Toxic effect; Translations; Work; amino group; biomaterial compatibility; combinatorial; combinatorial chemistry; cytotoxicity; delivery vehicle; design; disorder prevention; fabrication; gene therapy; human disease; improved; in vivo; lipid nanoparticle; mRNA delivery; nanocarrier; novel; practical application; safety and feasibility; screening; self assembly; small molecule; success

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.

概括 基于mRNA的治疗药在预防疾病和 治疗。但是，其广泛的实际应用在很大程度上受到交付的限制 关注。阳离子脂质是用于mRNA递送的有效载体材料和 脂质分子的化学结构对于确定递送功效至关重要。 但是，目前，没有广泛的指导原则来理性脂质 分子结构设计以实现假定的生物学作用。整合 已经证明了组合化学和体外/体内筛查方法 有助于开发有效的脂质载体。综合已付出了巨大的努力 带有新型化学结构的新脂质。但是，尽管有所有有希望的结果， 目前，几乎所有目前开发的用于mRNA递送的阳离子脂质都包含一级， 次级，第三级或四季度氨基群，作为可与之相互作用的收费单元 货物mRNA。在这项研究中，我们建议开发两种新型的阳离子脂质 含硫和磷的头部的分子和可生物降解的尾巴 并探索他们在体外mRNA传递中的应用。我们的假设是相反 对于传统的基于胺的阳离子脂质，硫酸和磷的脂质 将具有前所未有的自组装行为，mRNA传递性能，细胞 靶向和生物相容性曲线。通过使用组合库合成策略， 体外筛选方法和配方优化方法，该项目是第一个 开发可生物降解的可生物降解磺硫和磷的脂质并探索它们 细胞内mRNA递送的可行性和安全性。开发了新的脂质材料 在这项研究中，也可以在以后的研究中使用其他类型的治疗剂， 例如小分子药物，蛋白质和基因。