CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation

Abstract

Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular α‐synuclein (aSYN) binding to the cluster of differentation 36 (CD36) receptor. Herein, CD36‐binding nanoparticles (NPs) containing tartaric acid–based amphiphilic macromolecules (AMs) are rationally designed to inhibit this aSYN–CD36 binding. In silico docking reveals that four AMs with varying alkyl side chain lengths present differential levels of CD36 binding affinity and that an optimal alkyl chain length promotes the strongest inhibitory activity toward aSYN–CD36 interactions. In vitro competitive binding assays indicate that the inhibitory activity of AM‐based NPs plateaus at intermediate side chain lengths of 12 and 18 carbons, supporting the in silico docking predictions. These intermediate‐length AM NPs also has significantly stronger effects on reducing aSYN internalization and inhibiting proinflammatory molecules tumor necrosis factor α (TNF‐α) and nitric oxide from aSYN‐challenged microglia. All four NPs modulate the gene expression of aSYN‐challenged microglia, downregulating proinflammatory genes TNF, interleukin 6 (IL‐6), and IL‐1β, and upregulating anti‐inflammatory genes transforming growth factor β (TGF‐β) and Arg1 expression. Herein, overall, a novel polymeric nanotechnology platform is represented that can be used to modulate aSYN‐induced microglial activation.

Biomaterial strategies for regulating the neuroinflammatory response

“…Amphiphilic macromolecule-based nanoparticles have been developed with a tunable binding affinity for CD36, a class B scavenger receptor that mediates microglial activation. 186 Optimization of the alkyl side chain length in the polymer core increased binding of the nanoparticles to CD36, inhibiting microglial interactions with a-synuclein aggregates, which are known to propagate inflammatory signaling in Parkinson's disease. 87,186 In another study, chitosan nanocarriers were modified with fucoidan, 187 a sulfated amphiphilic polysaccharide that is known to target P-selectin, 188 a cell adhesion molecule used to recruit macrophages to an inflammatory environment.…”

“…186 Optimization of the alkyl side chain length in the polymer core increased binding of the nanoparticles to CD36, inhibiting microglial interactions with a-synuclein aggregates, which are known to propagate inflammatory signaling in Parkinson's disease. 87,186 In another study, chitosan nanocarriers were modified with fucoidan, 187 a sulfated amphiphilic polysaccharide that is known to target P-selectin, 188 a cell adhesion molecule used to recruit macrophages to an inflammatory environment. 189,190 Chitosan is particularly responsive to acidic environments, promoting accumulation of chitosan nanoparticles in acidic inflammatory tissue sites.…”

“…189,190 Chitosan is particularly responsive to acidic environments, promoting accumulation of chitosan nanoparticles in acidic inflammatory tissue sites. 186 Semiconducting polymer nanoparticles contain polymers with large p-conjugated rigid backbones. These conjugated polymers can efficiently produce heat or singlet oxygen when exposed to near-infrared light, allowing for activation of heatand oxygen-responsive therapeutics.…”

“…189,190 Chitosan is particularly responsive to acidic environments, promoting accumulation of chitosan nanoparticles in acidic inflammatory tissue sites. 186…”

Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology

“…We have previously designed a new class of amphiphilic macromolecules (AMs) composed of sugar-based backbones, aliphatic side chains, and hydrophilic poly (ethylene glycol) (PEG); these were conceived to be biomimetic synthetic ligands for lowering the SR–α-synuclein (α-syn) interactions and the subsequent microglial inflammatory response [ 48 – 50 ]. Due to their amphiphilic nature, AMs can be complexed around hydrophobic core molecules via kinetic flash nanoprecipitation (FNP), forming nanoparticles (NPs).…”