Athero-inflammatory nanotherapeutics: Ferulic acid-based poly(anhydride-ester) nanoparticles attenuate foam cell formation by regulating macrophage lipogenesis and reactive oxygen species generation

Abstract

Enhanced bioactive anti-oxidant formulations are critical for treatment of inflammatory diseases, such as atherosclerosis. A hallmark of early atherosclerosis is the uptake of oxidized low density lipoprotein (oxLDL) by macrophages, which results in foam cell and plaque formation in the arterial wall. The hypolipidemic, anti-inflammatory, and antioxidative properties of polyphenol compounds make them attractive targets for treatment of atherosclerosis. However, high concentrations of antioxidants can reverse their anti-atheroprotective properties and cause oxidative stress within the artery. Here, we designed a new class of nanoparticles with anti-oxidant polymer cores and shells comprised of scavenger receptor targeting amphiphilic macromolecules (AMs). Specifically, we designed ferulic acid-based poly(anhydride-ester) nanoparticles to counteract the uptake of high levels of oxLDL and regulate reactive oxygen species generation (ROS) in human monocyte derived macrophages (HMDMs). Compared to all compositions examined, nanoparticles with core ferulic acid-based polymers linked by diglycolic acid (PFAG) showed the greatest inhibition of oxLDL uptake. At high oxLDL concentrations, the ferulic acid diacids and polymer nanoparticles displayed similar oxLDL uptake. Treatment with the PFAG nanoparticles downregulated the expression of macrophage scavenger receptors, CD-36, MSR-1, and LOX-1 by about 20-50%, one of the causal factors for the decrease in oxLDL uptake. The PFAG nanoparticle lowered ROS production by HMDMs, which is important for maintaining macrophage growth and prevention of apoptosis. Based on these results, we propose that ferulic acid-based poly(anhydride ester) nanoparticles may offer an integrative strategy for the localized passivation of the early stages of the atheroinflammatory cascade in cardiovascular disease.

Facile assembly and loading of theranostic polymersomes via multi-impingement flash nanoprecipitation

“…Mixing occurs over millisecond timescales and is followed by transfer to a reservoir of aqueous nonsolvent to strip away solvent still associating with the aggregated drug and block copolymer. Modifications of this protocol has resulted in the rapid, scalable formation of a variety of nanocolloids with hydrophobic cores containing therapeutics and imaging agents with low water solubility [11–13], and only rarely for hydrophilic and ionic molecules [14]. While recent focus has been placed on this process of competitive aggregation for the scalable loading of nanoparticles with hydrophobic drugs, FNP was originally applied to achieve rapid changes in solvent quality for homogenous precipitation and self-assembly of block copolymers to investigate the mechanism and kinetics of micellization [15].…”

Nanotechnological approach to delivering nutraceuticals as promising drug candidates for the treatment of atherosclerosis

“…Polyphenolic compounds pose as attractive targets for atherosclerosis treatment imparting anti-inflammatory and anti-oxidative properties. Ferulic acid is a potent antioxidant that has been used to synthesize NPs with anti-oxidant polymeric cores decorated with amphiphilic macromolecules (PFAG) targeting scavenger receptors to analyze its therapeutic efficacy against athero-protection by minimizing Ox-LDL uptake and decelerate foam cell formation (Chmielowski et al, 2017). The controlled release of ferulic acid from the PFAG NPs generated excellent athero-protective nature by inhibiting Ox-LDL uptake amongst the other ferulic acid intermediate polymeric nano-formulations.…”

“…The controlled release of ferulic acid from the PFAG NPs generated excellent athero-protective nature by inhibiting Ox-LDL uptake amongst the other ferulic acid intermediate polymeric nano-formulations. The PFAG NPs downregulated the gene expression of macrophage scavenger receptors such as MSR-1, CD-36, and LOX-1 and minimized ROS levels in human monocyte-derived macrophages (HMDM) (Chmielowski et al, 2017). Chronic inflammation is an underlying disease pathology in atherosclerosis that could be bridled with the delivery of anti-inflammatory cytokine IL-10.…”

Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases

“…ROS-scavenging nanotherapies have demonstrated great potential in the prevention and treatment of cardiovascular disease. They can protect cardiac progenitor cells from oxidative stress (Pagliari et al, 2012), prevent ROS-induced death of implanted mesenchymal stem cells for myocardial infarction treatment (Park et al, 2015), and eliminate excessive ROS to mitigate atherosclerosis (Chmielowski et al, 2017;Wang et al, 2018). As a typical example, our previously developed TPCD nanoparticles significantly attenuated ROSinduced inflammation and cell apoptosis in macrophages, by eliminating broad-spectrum ROS in cells Wang et al, 2018).…”