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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

基本信息

批准号：
10685412
负责人：
Annaliese Franz
金额：
$ 7.65万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10685412
关键词：
Alkenes Biological Biomedical Research COVID-19 vaccination COVID-19 vaccine Carbon Cells Chemicals Chemistry Collaborations Collection Communicable Diseases Comparative Study Complex Discipline Disease Drug Delivery Systems Drug Formulations Elements Encapsulated Endosomes 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 biophysical properties cis trans isomerization cytotoxicity delivery vehicle design disability disorder prevention economic impact experimental study fighting fluidity 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

项目摘要

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