Cationic Silyl-lipids for Enhanced Delivery of Anti-viral RNA Therapeutics

用于增强抗病毒 RNA 治疗药物递送的阳离子甲硅烷基脂质

• 批准号: 10511399
• 负责人: Annaliese Franz
• 金额: $ 7.36万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511399
• 关键词: Alkenes; Biological; Biomedical Research; COVID-19; COVID-19 vaccination; COVID-19 vaccine; Carbon; Cations; Cells; Chemicals; Chemistry; Collaborations; Collection; Communicable Diseases; Comparative Study; Complex; Discipline; Disease; Drug Delivery Systems; Drug Formulations; Elements; Formulation; Future; Genetic Vectors; Goals; Health; High Pressure Liquid Chromatography; Human; Hydrophobicity; Industrialization; Laboratories; Length; Life; Lipids; Liposomes; Mammalian Cell; Measurement; Measures; Membrane; Membrane Fluidity; Messenger RNA; Methods; Mission; Molecular Conformation; Nucleic Acids; Oligonucleotides; Phase Transition; Plasmids; Play; Positioning Attribute; Property; Public Health; RNA; RNA delivery; Reporter; Research; Resources; Roentgen Rays; Role; Silicon; Small Interfering RNA; Structure; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Transfection; Transition Temperature; Transmission Electron Microscopy; United States National Institutes of Health; Unsaturated Fats; Vaccine Therapy; Work; analog; anti-viral efficacy; base; biophysical properties; cis trans isomerization; cytotoxicity; delivery vehicle; design; disability; disorder prevention; economic impact; experimental study; fighting; fluidity; health economics; improved; in vivo; innovation; lipid nanoparticle; lipophilicity; mRNA delivery; nanoparticle; novel; oxidative damage; pandemic preparedness; pi bond; public health relevance; response; success; therapeutic RNA; uptake; vaccine delivery; vector; viral RNA; weapons; zeta potential

PROJECT ABSTRACT Liposomes, including nucleic acid complexed lipid nanoparticles (LNPs) have shown success in drug delivery and formulation of sensitive RNA-based therapeutics, including the recent example of the mRNA Sar-COV-2 vaccine. The goal of this proposal is to synthesize and evaluate novel silyl-containing lipid structures to access innovative cationic lipid structures representing new chemical space for biomedical research. Three classes of cationic silyl-lipids will be synthesized in modular fashion to access structural and conformational cationic lipid analogs that have implications in the phase transition temperature and the fluidity of the bilayer, influencing the stability, toxicity, and fusogenicity of silyl- LNPs. This proposal is organized into three specific aims: 1) Synthesis of novel silyl-containing lipids as diverse cationic lipid vectors using catalytic hydrosilylation methods, particularly focusing on the modular incorporation of a silyldimethyl group as a bioisostere of a cis carbon–carbon double bond of known unsaturated cationic lipid vectors, as well as other silyl groups with relevant properties to modulate the branching and chain length of the resulting lipid. Target molecules include silyl analogs of DOTMA, DOTAP and DOSPA. 2) Evaluate biophysical properties of liposome formation and silyl-LNP formulation through established characterization techniques including measurements of zeta potential, transmission electron microscopy and small-angle X-ray scattering. The RNA/silyl-LNP complex will be characterized using HPLC to quantify RNA encapsulation. 3) Perform in cellulo studies to provide a comparative study on transfection efficacy of siRNA and cytotoxicity of silyl-lipid LNPs with commercially available liposome RNA delivery systems. Overall, our studies aim to demonstrate the potential of cationic silyl-lipids as novel structures for LNP formulation with the long-term goal to develop novel delivery systems and improve transfection efficacy of anti-viral RNA therapeutics.

项目摘要 脂质体，包括核酸复合脂质纳米粒子（LNP），已在药物领域取得了成功 基于 RNA 的敏感疗法的递送和配制，包括最近的例子 mRNA Sar-COV-2 疫苗。该提案的目标是合成和评估新型含硅基化合物 脂质结构以获得代表新化学空间的创新阳离子脂质结构 生物医学研究。三类阳离子甲硅烷基脂质将以模块化方式合成 获得对相变有影响的结构和构象阳离子脂质类似物 温度和双层的流动性，影响硅基的稳定性、毒性和融合性 LNP。该提案分为三个具体目标：1）合成新型含甲硅烷基脂质 作为使用催化氢化硅烷化方法的多种阳离子脂质载体，特别关注 甲硅烷基二甲基作为顺式碳-碳双键的生物电子等排体的模块化结合 已知的不饱和阳离子脂质载体，以及具有相关特性的其他甲硅烷基基团 调节所得脂质的支链和链长。目标分子包括以下的甲硅烷基类似物 DOTMA、DOTAP 和 DOSPA。 2) 评估脂质体形成和甲硅烷基-LNP的生物物理特性 通过已建立的表征技术（包括 zeta 电位测量）进行配方， 透射电子显微镜和小角X射线散射。 RNA/甲硅烷基-LNP 复合物将是 使用 HPLC 来量化 RNA 封装的特征。 3）进行大提琴研究以提供 siRNA转染效果及硅脂LNPs与市售产品的细胞毒性对比研究 可用的脂质体 RNA 递送系统。总的来说，我们的研究旨在展示 阳离子甲硅烷基脂质作为 LNP 配方的新型结构，长期目标是开发新型 递送系统并提高抗病毒 RNA 疗法的转染功效。