Design of antioxidant nanotherapeutics for attenuation of atherogenesis and neuroinflammation

Atherosclerosis and Parkinson’s disease are both characterized by the uncontrolled uptake of modified proteins in chronic inflammatory cells, macrophages/microglia. The initial stages of atherosclerosis are characterized by oxidation of low density lipoprotein and its uptake by macrophages, which can lead to plaque progression in the arterial wall and possibly heart attack or stroke. Formation and increase of misfolded aggregates of proteins such as alpha synuclein (α-synuclein) are a key factor in several neurodegenerative diseases including Parkinson’s disease. Both classes of diseases are exacerbated in macrophages/microglia due to a strong inflammatory component, which has been challenging to treat. The anti-atheroprotective and anti-inflammatory properties of antioxidants create an attractive target for treatment of atherosclerosis and Parkinson’s disease. We propose a library of antioxidant nanoparticles that have the potential to address critical needs for both atherosclerosis and Parkinson’s disease. For atherosclerosis applications, we advanced the delivery and formulation of antioxidants through the development of ferulic acid-based polymer nanoparticles, which are completely biodegradable and can achieve a sustained and tunable release of ferulic acid to limit macrophage foam cell formation. The ferulic acid-based polymer nanoparticles attenuated macrophage lipogenesis and reactive oxygen species generation. The cellular mechanism of the nanoparticle efficacy involved the down regulation of the expression of three scavenger receptors, which are critical for modulation of lipid uptake in macrophages. For neuroinflammatory applications, we developed a dual antioxidant nanoparticle consisting of ferulic acid and tannic acid, which significantly reduced the generation of -synuclein fibrils. This result suggests that the combination of antioxidants and the configuration of nanoparticle vehicles could be important factors for inhibiting -synuclein fibril formation. Overall, antioxidant nanotherapeutics may be promising technologies for inhibition of early stages of both atherosclerosis and Parkinson’s disease.Ph.D.Includes bibliographical referencesby Rebecca Ann Chmielowsk