(375d) Design of Nanoparticle Charge and Architecture for Modulation of Cell-Ldl Interactions Underlying Atherogenesis

Atherosclerosis, a major determinant of vascular disease, is triggered by the pathologic build-up of low-density lipoproteins (LDL) within the vascular intima and subsequent interactions between macrophages and their extracellular matrix molecules. The progression towards disease begins with LDL, the major carrier of cholesterol in the blood plasma, which enters the arterial wall through the injured endothelium and is sequestered by extracellular matrix molecules, such as proteoglycans. In the intima, LDL is chemically and oxidatively modified before release, whereupon LDL is accessible to intimal macrophages. Oxidized LDL (oxLDL) uptake is mediated by scavenger receptors and unlike the receptors for native LDL, scavenger receptors are typically not downregulated leading to unregulated cholesterol accumulation, and resulting in the formation of foam cells and the formation of fatty streaks which are the earliest visible atherosclerotic lesions. Most therapeutic approaches focus on inhibiting the synthesis of lipoproteins and do not target the management of LDL sequestered within the intima. In an effort to inhibit oxLDL uptake by macrophages and alleviate atherosclerosis, nanoscale amphiphilic particles (NAP) have been designed to block scavenger receptors and in turn prevent the binding of oxLDL. The nanoparticles consist of a hydrophobic region (alkyl chains), a hydrophilic component (methoxy-poly(ethylene glycol) chains), a mucic acid backbone and form micelles in solution at concentrations greater than 10-7 M. When functionalized with an anionic group on the mucic acid, these nanoparticles have been shown to inhibit oxLDL uptake by 75%. In addition, it has been shown that the major scavenger receptors responsible for the uptake of oxLDL are SR-A and CD36. In an effort to improve the inhibitory potential of the nanoparticles, new polymers have been designed with varying charge densities and charge presentations. To fully understand how the current NAPs are interacting with scavenger receptors and as new designs of NAPs are developed a quantitative comparison is necessary. Thus, in addition to oxLDL uptake experiments, a closer look is needed at the scavenger receptor-NAP interface. This will be accomplished by means of binding affinity measurements so as to compare the strength of each nanoparticle-scavenger receptor interaction. The binding affinity will be measured using a quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance (SPR). Through the creation of a new class of scavenger receptor blockers and a quantitative look at the binding kinetics, the NAP design will be optimized for the design of improved therapeutic approaches for management of atherosclerosis.