title: Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation.
abstract: Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Iverson
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Plourde
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Sparks
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Wang
authors.forename: Ekta N
authors.initials: EN
authors.lastname: Patel
authors.forename: Pratik S
authors.initials: PS
authors.lastname: Shah
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lewis
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Zablocki
authors.forename: Gary B
authors.initials: GB
authors.lastname: Nackman
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D046911:Macromolecular Substances / Q000737:chemistry*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053758:Nanoparticles; D057093:Orphan Nuclear Receptors / Q000819:agonists; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D046911:Macromolecular Substances; D057093:Orphan Nuclear Receptors; D051117:Scavenger Receptors, Class A; D013501:Surface-Active Agents; C099252:oxidized low density lipoprotein; D002784:Cholesterol