Multifunctional polymers for inhibition of oxidized lipoprotein accumulation and inflammation in macrophage cells

A major cause of cardiovascular disease is atherosclerosis, the progressive accumulation and modification of low density lipoproteins (LDL) within the vascular wall associated with a non-reversible inflammatory cascade. Current treatments attempt to inhibit systemic LDL levels, and thus can only secondarily de-escalate the progression of atherosclerosis. This thesis investigates the mechanisms of an alternative approach based on the use of amphiphilic polymers to directly inhibit highly oxidized LDL (hoxLDL) internalization by macrophage cells, thereby retarding foam cell formation and inflammatory cytokine secretion. First the architecture of the polymers is systematically investigated to elucidate the important design facets for hoxLDL uptake inhibition by THP-1 human macrophage cells in serum and serum free media. The optimal polymer structure is found to be comprised of one, rotationally restricted carboxylic acid conjugated to the hydrophobic end of each polymer chain. Through the administration of carboxy-terminated amphiphilic polymers (AMs) the total concentration of hoxLDL within macrophage cells is lowered by 73% and when an encapsulated Liver-X Receptor (LXR) ligand is also delivered the hoxLDL accumulation is further lowered, decreased by 88%. The delivery of the AMs and drug encapsulated AMs in vivo shows a significant inhibition in cholesterol accumulation and macrophage recruitment in an injured carotid artery rat model. The AMs also inhibit inflammatory responses in vitro, significantly decreasing matrix metalloproteinase (57%) and cytokine secretion (TNFα 47% and IL-1β 59%) compared to non-treated cells. Through the inhibition of hoxLDL internalization and inflammation progression these AMs show the potential to be a new and multi-faceted cardiovascular treatment modality.Ph.D.Includes abstractVitaIncludes bibliographical referencesby Nicole M Iverso