Document text
Principal Investigator: Annaliese Franz
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2023
Award: $76,496
Funding agency: National Institute of Biomedical Imaging and Bioengineering
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.
Terms: <2019-nCoV vaccine><Alkenes><Bilayer Fluidity><Biological><Biomedical Research><COVID-19 vaccination><COVID-19 vaccine><COVID19 vaccination><COVID19 vaccine><Carbon><Cell Body><Cells><Chemicals><Chemistry><Collaborations><Collection><Communicable Diseases><Comparative Study><Complex><Discipline><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Formulations><Elements><Encapsulated><Endosomes><Formulation><Future><Genetic Vectors><Goals><HPLC><Health><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Human><Hydrophobicity><Industrialization><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Laboratories><Length><Life><Lipids><Liposomal><Liposomes><Lytotoxicity><Mammalian Cell><Measurement><Measures><Membrane><Membrane Fluidity><Messenger RNA><Methods><Mission><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><NIH><National Institutes of Health><Non-Polyadenylated RNA><Nucleic Acids><Olefins><Oligo><Oligonucleotides><Phase Transition><Plasmids><Play><Position><Positioning Attribute><Property><Public Health><RNA><RNA Gene Products><RNA based therapeutics><RNA based therapy><RNA delivery><RNA therapy><Receptosomes><Reporter><Research><Research Resources><Resources><Ribonucleic Acid><Roentgen Rays><Role><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Short interfering RNA><Si element><Silicon><Small Interfering RNA><Structure><System><Techniques><Technology><Therapeutic><Therapeutic Effect><Toxic effect><Toxicities><Transfection><Transition Temperature><Transmission Electron Microscopy><United States National Institutes of Health><Unsaturated Fats><VAC-TX><Vaccine Therapy><Work><X-Radiation><X-Ray Radiation><X-ray><Xray><analog><anti-viral efficacy><antiviral efficacy><biologic><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cis trans isomerization><conformation><conformational><conformational state><conformationally><conformations><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cytotoxicity><deliver vaccines><delivery vector><delivery vehicle><design><designing><disability><disease prevention><disorder prevention><double bond><economic impact><experiment><experimental research><experimental study><experiments><fighting><fluidity><improved><in vivo><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><lipophilicity><mRNA><mRNA delivery><membrane structure><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle><nano-sized particle><nanoparticle><nanosized particle><novel><oligos><oxidative damage><oxidative injury><pandemic disease preparedness><pandemic planning><pandemic preparedness><pandemic readiness><pi bond><public health relevance><response><siRNA><social role><success><therapeutic RNA><therapeutic vaccination><transfection vector><unsaturated dietary fat><unsaturated dietary lipid><unsaturated lipid><uptake><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine delivery><vaccine for novel coronavirus><vector><viral RNA><virus RNA><weapons><zeta potential>