The use of lipid nanoparticles (LNPs) for drug delivery offers exciting new avenues for gene therapy. The LNP’s cationic lipid (XTC2) and anionic endosomal lipids such as lysobisphosphatidic acid (LBPA) are hypothesized to form non-bilayer phases which promote cargo release into the cytoplasm. However, this release is inefficient in current formulations. Computer simulations based on accurate lipid models could be used to predict LNP formulations having improved release efficacy. The inverted hexagonal (Hii) phase of dioleoylphosphatidylethanolamine was studied with small angle X-ray scattering (SAXS) and deuterium nuclear magnetic resonance (NMR) to provide lattice repeat spacing and acyl chain order parameters for simulations. Physical characteristics of LBPA and XTC2 forming non-bilayer phases were measured as functions of temperature and pH using SAXS and phosphorus NMR. In particular, under acidic conditions, an equimolar mixture of LBPA/XTC2 exhibited Hii and cubic phases that could enhance the release of cargo from the LNP.
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Thesis advisor: Thewalt, Jenifer
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