Amphiphilic macromolecule therapeutics to manage cardiovascular disease

The hypothesis of this research is that atherosclerosis, the principal pathology underlying vascular occlusive disease, can be targeted and moderated using Amphiphilic Macromolecules (AMs). By mimicking the amphiphilicity and charge distribution of oxidized LDL, AMs can mitigate its downstream consequences by competitively blocking interaction with scavenger receptors. This work evaluated the ability of AM of various chemical compositions and architectures to reduce lipid accumulation in macrophages. Insights from these studies were used in conjunction with 3D molecular descriptors to identify the features of AM with most anti-atherogenic potency. To further develop AM as a viable therapeutic modality, these features were incorporated into kinetically fabricated nanoparticles (NPs) that are non-inflammatory and resist serum binding. An atherosclerotic animal model was established and used to examine the in vivo biodistribution and pharmacokinetic profile of systemically circulating AM NPs in addition to their ability to localize to lesions and stabilize plaques. Collectively, these outcomes establish AM as a multimodal nanotherapeutic platform designed to target atherosclerotic lesions and inhibit inflammation and atherogenesis. This thesis is comprised of three principal research aims: 1) To determine quantitative structure-activity relationships between Amphiphilic Macromolecule architecture and in vitro reductions in oxidized LDL uptake and lipid accumulation in macrophages; 2) To develop AM into non-inflammatory serum-stable nanoparticles (AM NPs); 3) To study the in vivo dynamics of systemically injected AM NPs and examine their ability to target atherosclerotic lesions and mitigate plaque development.Ph. D.Includes bibliographical referencesby Daniel Raiken Lewi