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，包括核酸复合的脂质纳米颗粒（LNP）已经显示出在药物治疗中的成功。 敏感的基于RNA的治疗剂的递送和制剂，包括最近的 mRNA Sar-COV-2疫苗。本提案的目标是合成和评价新型含甲硅烷基的 脂质结构，以获得创新的阳离子脂质结构，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甲硅烷基脂质， 访问结构和构象的阳离子脂质类似物，具有相变的影响 温度和双分子层的流动性，影响甲硅烷基- LNP。本研究的主要目的是：1）合成新型含硅基的脂质体 作为不同的阳离子脂质载体，使用催化氢化硅烷化方法，特别关注 作为顺式碳-碳双键的生物电子等排体的甲硅烷基二甲基基团的模块化并入， 已知的不饱和阳离子脂质载体以及具有相关性质的其它甲硅烷基， 调节所得脂质的分支和链长。靶分子包括甲硅烷基类似物， DOTMA、DOTAP和DOSPA。2)评价脂质体形成和甲硅烷基-LNP的生物物理性质 通过已建立的表征技术包括ζ电位的测量来配制， 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表征以定量RNA包封。3)在细胞内进行研究， 硅基脂质LNPs与市售LNPs的siRNA转染效率和细胞毒性的比较研究 可用的脂质体RNA递送系统。总的来说，我们的研究旨在证明 作为LNP制剂的新型结构的阳离子甲硅烷基脂质的长期目标是开发新型的 本发明的目的在于提供一种用于递送系统的抗病毒RNA治疗剂，并提高抗病毒RNA治疗剂的转染功效。