Pathologies in blood vessels arising from the uncontrolled build-up of oxidized lipids contribute to atherosclerosis, a severe cardiovascular disease, which underlies the most common cause of adult death in the U.S. (exceeding one million patients yearly). Few existing therapeutic strategies address the local management of atherogenesis (build-up of oxidized lipids in the blood vessel walls) and related inflammation. The overall goals of this study are to rationally design and characterize nanoscale biomaterials as a novel cell-targeted materials platform for investigating strategies to de-escalate the onset of atherogenesis and reduce accompanying inflammation. The proposed NIH R21 study involves three specific objectives to investigate nanoassembled amphiphilic polymers (NAPs) to maximally inhibit oxidized LDL uptake in human macrophages under physiologic conditions and exhibit potential for specific targeting to inflamed endothelia. Efforts in Aim 1 will involve investigation of innovative designs of nano-assembled amphiphilic polymers (NAP) composition and architecture to promote NAP binding to both SRA-1 and CD36 scavenger receptors on human THP-1 macrophages and thus inhibit uptake of oxidized low-density lipoproteins (oxLDL). New configurations of NAP will tested for improved lipid uptake inhibition in the presence of serum. Studies in Aim 2 will investigate the effect of NAP-scavenger receptor (SR) interactions on the downstream intracellular and cell-secreted intermediates regulating atherogenesis in macrophages, including cytokine secretion;cholesterol ester accumulation;matrix metalloproteinase secretion;and expression analysis of genes involved in pro-atherogenic signaling pathways.
Aim 3 is concerned with design and evaluation of the potential of biofunctionalized NAPs to bind to and transport across activated endothelial cell cultures in vitro, thereby creating a simplified in vitro model of the rescue of macrophage cells involved in atherogenesis within the vascular intima.

Public Health Relevance

The excessive uptake of modified forms of LDL in immune blood cells macrophages is one of the hallmarks of fat build-up and vascular disease within blood vessel walls, which can lead to blockage of blood flow, and cause heart disease or stroke. This study will investigate the design of nanoscale assembled polymers with specific architectures, charge displays, and chemistry so as to reduce the uptake of the most damaging forms of lipoproteins within macrophages. The goals of the study are to identify the most effective """"""""nanolipoblocker"""""""" configurations that may prevent atherogenesis by targeting activated blood vessel cells and blocking foam cell formation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL093753-01A2
Application #
7661126
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Danthi, Narasimhan
Project Start
2009-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
1
Fiscal Year
2009
Total Cost
$225,669
Indirect Cost
Name
Rutgers University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Chmielowski, Rebecca A; Abdelhamid, Dalia S; Faig, Jonathan J et al. (2017) Athero-inflammatory nanotherapeutics: Ferulic acid-based poly(anhydride-ester) nanoparticles attenuate foam cell formation by regulating macrophage lipogenesis and reactive oxygen species generation. Acta Biomater 57:85-94
Lewis, Daniel R; Petersen, Latrisha K; York, Adam W et al. (2016) Nanotherapeutics for inhibition of atherogenesis and modulation of inflammation in atherosclerotic plaques. Cardiovasc Res 109:283-93
Lewis, Daniel R; Petersen, Latrisha K; York, Adam W et al. (2015) Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo. Proc Natl Acad Sci U S A 112:2693-8
Petersen, Latrisha K; York, Adam W; Lewis, Daniel R et al. (2014) Amphiphilic nanoparticles repress macrophage atherogenesis: novel core/shell designs for scavenger receptor targeting and down-regulation. Mol Pharm 11:2815-24
Lewis, Daniel R; Kholodovych, Vladyslav; Tomasini, Michael D et al. (2013) In silico design of anti-atherogenic biomaterials. Biomaterials 34:7950-9
Tomasini, Michael D; Zablocki, Kyle; Petersen, Latrisha K et al. (2013) Coarse grained molecular dynamics of engineered macromolecules for the inhibition of oxidized low-density lipoprotein uptake by macrophage scavenger receptors. Biomacromolecules 14:2499-509
York, Adam W; Zablocki, Kyle R; Lewis, Daniel R et al. (2012) Kinetically assembled nanoparticles of bioactive macromolecules exhibit enhanced stability and cell-targeted biological efficacy. Adv Mater 24:733-9
Iverson, Nicole M; Plourde, Nicole M; Sparks, Sarah M et al. (2011) Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation. Biomaterials 32:8319-27
Lewis, Daniel R; Kamisoglu, Kubra; York, Adam W et al. (2011) Polymer-based therapeutics: nanoassemblies and nanoparticles for management of atherosclerosis. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:400-20
Iverson, Nicole M; Sparks, Sarah M; Demirdirek, Bahar et al. (2010) Controllable inhibition of cellular uptake of oxidized low-density lipoprotein: structure-function relationships for nanoscale amphiphilic polymers. Acta Biomater 6:3081-91

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