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(LNPs)，已经在药物方面取得了成功 提供和配制敏感的基于RNA的疗法，包括最近的例子 SARS-COV-2基因疫苗。本方案的目标是合成和评价新型含硅基化合物。 脂类结构以获得创新的阳离子类脂结构，代表新的化学空间 生物医学研究。将以模块化方式合成三类阳离子硅基脂类，以 获得在相变中有意义的结构和构象阳离子类脂类似物 温度和双层的流动性，影响硅基的稳定性、毒性和融合性- LNPs。该方案分为三个具体目标：1)合成新型含硅基脂类 作为各种阳离子脂类载体使用的催化硅氢加成方法，特别是侧重于 硅基二甲基团作为顺式碳-碳双键的生物等价体的模块化掺入 已知的不饱和阳离子脂载体，以及其他具有相关性质的硅基 调节所产生的脂类的分支和链长。目标分子包括硅基类似物 DOTMA、DOTAP和DOSPA。2)评价脂质体形成和硅基-LNP的生物物理性质 通过包括测量Zeta电位在内的已建立的表征技术进行配方， 透射电子显微镜和小角X射线散射。RNA/Silyl-LNP复合体将是 采用高效液相色谱定量RNA包封率进行表征。3)在纤维素学研究中表演，以提供 市售硅脂类LNPs对siRNA的转染效率及细胞毒性的比较研究 现有的脂质体RNA递送系统。总体而言，我们的研究旨在证明 阳离子硅脂作为LNP制剂的新结构，长期目标是开发新的 并提高抗病毒RNA治疗药物的转染率。