Polymer brain-nanotherapeutics for multipronged inhibition of microglial α-synuclein aggregation, activation, and neurotoxicity

Abstract

Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers. Next, we designed a nanotechnology approach to regulate SR-mediated intracellular ASYN trafficking within microglia. We synthesized mucic acid-derivatized sugar-based amphiphilic molecules (AM) with optimal stereochemistry, rigidity, and charge for enhanced dual binding affinity to SRs and fabricated serum-stable nanoparticles via flash nanoprecipitation comprising hydrophobe cores and amphiphile shells. Treatment of microglia with AM nanoparticles decreased monomeric ASYN internalization and intracellular ASYN oligomer formation. We then engineered composite deactivating NPs with dual character, namely shell-based SR-binding amphiphiles, and core-based antioxidant poly (ferrulic acid), to investigate concerted inhibition of oxidative activation. In ASYN-challenged microglia treated with NPs, we observed decreased ASYN-mediated acute microglial activation and diminished microglial neurotoxicity caused by exposure to aggregated ASYN. When the composite NPs were administered in vivo within the substantia nigra of fibrillar ASYN-challenged wild type mice, there was marked attenuation of activated microglia. Overall, SR-targeting AM nanotechnology represents a novel paradigm in alleviating microglial activation in the context of synucleinopathies like PD and other neurodegenerative diseases.

Microglia-targeting nanotherapeutics for neurodegenerative diseases

“…In vivo studies in a PD mouse model showed that the AM NPs can reduce ASYN deposition in the CNS as well as reduce microglial activation and recruitment, which were achieved by the combinatorial effect of the scavenger receptor-targeting AM shell and anti-inflammatory ferulic acid polymer components. 189 This result highlights the use of NP formulations as a unique drug delivery platform, which not only supports but also strengthens the activity of the bioactive agent and enables targeted delivery.…”

“…One example is a scavenger receptor-targeting amphiphilic macromolecule-based NP (AM NP) design, carrying ferulic acid-derived polymer as a therapeutic agent. 189 These AM NPs were designed to have strong affinity to scavenger receptors, specifically CD36 and SR-A1 on microglia, and can weaken the receptor binding of ASYN, thus reducing ASYN aggregation-induced microglial activation. In vivo studies in a PD mouse model showed that the AM NPs can reduce ASYN deposition in the CNS as well as reduce microglial activation and recruitment, which were achieved by the combinatorial effect of the scavenger receptor-targeting AM shell and anti-inflammatory ferulic acid polymer components.…”

Recalcitrant Issues and New Frontiers in Nano-Pharmacology

“…An interesting least-component based approach of targeted drug delivery using bioactive polymers, wherein polymers are engineered to have targeting moieties, replacing the need of conjugating additional targeting ligands like antibodies, was developed by Prof Kathryn Uhrich (Gu et al, 2014; Zhang et al, 2015). Her team formulated a library of sugar-based amphiphiles with geometries similar to liposomes, hydrophobic core (to encapsulate drug), and hydrophilic shell, wherein the shell is engineered to have targeting moieties (Gu et al, 2014) and then screened these bioactive polymers for their anti-cancer and anti-Parkinson activities (Bennett et al, 2016; Gu et al, 2017).…”

PLGA Microspheres Loaded with β-Cyclodextrin Complexes of Epigallocatechin-3-Gallate for the Anti-Inflammatory Properties in Activated Microglial Cells

“…The inequality of these activation in microglial cells may lead to either neural benefit or damage. The activation of microglial cells in terms of chronicity is believed to be related to neurodegenerative disorders (Alzheimer’s disease [ 10 , 11 , 12 ] and Parkinson’s disease [ 13 , 14 , 15 ]). Hence, the inhibition of microglial activation has been suggested for potential treatment of neurodegenerative diseases [ 16 , 17 ].…”