Micelles and lipid nanoparticles: catalysis and biomedical application.

Abstract

RNA-based therapeutics is a rapidly expanding field due to its enormous potential for treatment of diseases through knockdown of genes or expression of therapeutic proteins. However, due to the overall negative-charge of an RNA molecule, RNA-based therapeutics must rely on delivery systems to overcome the various biological barriers for ultimate release of an RNA payload into the cytosol. Over the past three decades, the development of lipid-based RNA delivery systems, especially lipid nanoparticles (LNPs), have been comprehensively studied due to their unique properties. LNPs represent the most widely used delivery systems for RNA-based therapeutics, as evidenced by the clinical approvals of three LNP-RNA formulations: patisiran (ONPATTRO®), and BNT162b2 and mRNA-1273, which are LNP-encapsulated mRNA-based vaccines for prevention of COVID-19. Cationic lipids are also considered suitable candidates for RNAi therapeutics delivery. To this end, the present thesis work centers on examining liposome formulations of oxime ether (OELs) containing hydroxylated head groups in animal studies to validate their suitability as in vivo RNA carriers. This thesis work also examines the effects of adding a boron-containing lipid to OEL4-based formulations. Conjugation chemistry, particularly oximation, is a critical component for the development of these lipids. Oximation involves the reaction of an aminooxy group with a carbonyl group of an aldehyde or ketone to form an oxime ether. The versatility of oximation is highlighted and exploited in this thesis. In addition, as part of my initial studies on micelles, the synthesis and synthetic applications of a novel, environmentally benign surfactant developed to form micelles containing polar cores is also described. This thesis is divided into two parts. Part I focuses on the synthesis and applications of PS-750-M, a surfactant developed to enable organic synthesis transformations in water. Accordingly, Chapter 1 reviews the historical development of micellar catalytic processes. Chapter 2 details the synthesis of the surfactant PS-750-M and its application in Suzuki-Miyaura couplings of unactivated quinoline systems. PS-750-M contains a proline-based linker between its hydrophobic and hydrophilic regions that imparts polarity to the micellar core, which is presumed to play a significant metal-coordinating role in the micellar Suzuki-Miyaura coupling reactions. PS-750-M functions as a green solvent that mimics toxic dipolar-aprotic solvents, such as DMF, DMAc, NMP, and 1, 4-dioxane. The micellar reaction medium derived from PS-750-M is demonstrated to be recyclable. Part II focuses on the use of hydroxylated oxime ether lipids (OELs) as delivery agents for RNAi therapeutics. We first explore the in vivo