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Probing the Nanoscopic Thermodynamic Fingerprint of Paramagnetic Ligands Interacting with Amphiphilic Macromolecules.

ABSTRACT: Self-assembly of macromolecules with ligands is an intricate dynamic process that depends on a wide variety of parameters and forms the basis of many essential biological processes. We elucidate the underlying energetic processes of self-assembly in a model system consisting of amphiphilic core-shell polymers interacting with paramagnetic, amphiphilic ligand molecules from temperature-dependent continuous wave electron paramagnetic resonance (CW EPR) spectroscopy subsequent to spectral simulation. The involved processes as observed from the ligands' point of view are either based on temperature-dependent association constants (K_A,j,k) or dynamic rotational regime interconversion (IC) constants (K_IC,j,k). The interconversion process describes a transition from Brownian (b?) towards free (b?) diffusion of ligand. Both processes exhibit non-linear van't Hoff (lnK vs. T^-1) plots in the temperature range of liquid water and we retrieve decisive dynamic information of the system from the energetic fingerprints of ligands on the nanoscale, especially from the temperature-dependent interconversion heat capacity (?C°_P,IC).

SUBMITTER: Reichenwallner J

PROVIDER: S-EPMC6418530 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Probing the Nanoscopic Thermodynamic Fingerprint of Paramagnetic Ligands Interacting with Amphiphilic Macromolecules.

Reichenwallner Jörg J Schwieger Christian C Hinderberger Dariush D

Polymers 20170731 8

Self-assembly of macromolecules with ligands is an intricate dynamic process that depends on a wide variety of parameters and forms the basis of many essential biological processes. We elucidate the underlying energetic processes of self-assembly in a model system consisting of amphiphilic core-shell polymers interacting with paramagnetic, amphiphilic ligand molecules from temperature-dependent continuous wave electron paramagnetic resonance (CW EPR) spectroscopy subsequent to spectral simulatio ...[more]

PMID: 30971002

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Project description: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.

Dataset Information

Probing the Nanoscopic Thermodynamic Fingerprint of Paramagnetic Ligands Interacting with Amphiphilic Macromolecules.

Publications

Probing the Nanoscopic Thermodynamic Fingerprint of Paramagnetic Ligands Interacting with Amphiphilic Macromolecules.

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