Design, synthesis, and characterization of amphiphilic colloidal formulations for biomedical and personal care applications
Creators: name: Moretti, Alysha Eileen
Publisher: name: No Publisher Supplied
Year: 2017

description: Amphiphilic molecules comprised of a hydrophilic and hydrophobic domain are able to self-assemble into a variety of higher order aggregates.  These aggregate structures, and their diverse morphologies, have been utilized for the delivery of bioactive agents.  Additionally, amphiphiles can be tailored to exhibit inherent bioactivity.  This dissertation describes the design and synthesis of amphiphilic molecules that self-assemble into aggregate structures with defined physicochemical properties. Their formulation and biological activity for diverse biomedical and personal care applications are fully characterized.  Amphiphilic macromolecules (AMs) conjugated to ligands known to activate the G-coupled protein receptor TGR5 were investigated as nanoparticle (NP) formulations for the reduction of inflammation in atherosclerotic macrophages.  Macrophages propagate the atherosclerotic cascade by uncontrolled internalization of oxidized low-density lipoprotein (oxLDL) and subsequent secretion of inflammatory cytokines. AMs, based on an acylated sugar backbone conjugated to poly(ethylene glycol) (PEG), were synthesized containing a lithocholic acid (LCA) moiety, a known TGR5 agonist.  Ligand-conjugated AMs were formulated into NPs to mitigate the lipid burden and inflammatory phenotype by competitively inhibiting oxLDL uptake through scavenger receptor (SR) interactions and activating the athero-protective receptor TGR5.  Ligand-conjugated AM NPs significantly reduce oxLDL uptake compared to untreated controls and lower expression of inflammatory genes under direct control of TGR5.  These studies demonstrate the potential of ligand-conjugated AM NPs to reduce the atherosclerotic phenotype in activated macrophages.  Modifications were also made to AMs to enable their incorporation into distearoylphosphatidylcholine- (DSPC-) based liposomes for delivery applications.  Liposome use has aided in the bioavailability, solubility, and improved pharmacokinetic profiles of a wide variety of active ingredients for biomedical and personal care products.  This work expands upon the AM design to generate two series of molecules that simultaneously stabilize liposome colloidal properties and can be utilized to fine-tune release profiles of encapsulated cargo. Two series of AMs were synthesized with variations in their hydrophobic domains. All AMs improve upon stability properties at storage and physiological temperatures compared to DSPC-based liposomes alone. The chemical features of AMs, particularly the degree of unsaturation in the hydrophobic domain, influence release of hydrophilic molecules from liposomes’ interior.  Molecular dynamics (MD) simulations reveal that AMs’ chemical structures influence local lipid properties, leading to the experimentally observed results.  Together, this data offers insight that can be applied to design AMs with desirable physicochemical properties for bioactive delivery.  Small molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug resistant bacteria.  CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death.  Discrete structural features of CAms were varied and structure-activity relationship studies were performed to guide the rational design of potent antimicrobials with desirable selectivity and cytocompatibility profiles.  In particular, the effect of cationic conformational flexibility, hydrophobic domain flexibility, and hydrophobic domain architecture were evaluated.  Their influence on antimicrobial efficacy in Gram-positive and Gram-negative bacteria was determined, and their safety profiles established by assessing their impact on mammalian cells.  All CAms have potent activity against bacteria and hydrophobic domain rigidity and branched architecture contribute to specificity. The insights gained from this project will aid in the optimization of CAm structures.   Together, these three primary projects build upon the design of biocompatible amphiphiles that enable the delivery of bioactive molecules.  Thorough structure-activity relationship studies were performed in each chapter to identify and generate amphiphiles with desirable outcomes for the specific application.