PEGylated Nanoparticles Bind to and Alter Amyloid-Beta Peptide Conformation: Toward Engineering of Functional Nanomedicines for Alzheimer’s Disease

Abstract

We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aβ(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the interaction with monomeric and soluble oligomeric forms of Aβ(1-42) peptide was demonstrated by capillary electrophoresis, surface plasmon resonance, thioflavin T assay, and confocal microscopy, where the binding affected peptide aggregation kinetics. The capture of peptide by NPs in serum was also evidenced by fluorescence spectroscopy and ELISA. Moreover, in silico and modeling experiments highlighted the mode of PEG interaction with the Aβ(1-42) peptide and its conformational changes at the nanoparticle surface. Finally, Aβ(1-42) peptide binding to NPs affected neither complement activation in serum nor apolipoprotein-E (Apo-E) adsorption from the serum. These observations have crucial implications in NP safety and clearance kinetics from the blood. Apo-E deposition is of prime importance since it can also interact with the Aβ(1-42) peptide and increase the affinity of NPs for the peptide in the blood. Collectively, our results suggest that these engineered long-circulating NPs may have the ability to capture the toxic forms of the Aβ(1-42) peptide from the systemic circulation and potentially improve Alzheimer's disease condition through the proposed "sink effect".

Effect of nanoparticles binding ß-amyloid peptide on nitric oxide production by cultured endothelial cells and macrophages

“…25 In a series of investigations carried out within the framework of the FP7 EU project known as NAD (Nanoparticles for therapy and diagnosis of Alzheimer's Disease), we designed a series of lipid and polymer-based nanoparticles able to bind with high affinity to aggregate forms of β-amyloid peptide 1,2 and to reduce cytotoxicity 4 or aggregation of the peptide in vitro. 2,27 In order to evaluate cytotoxicity after administration in vivo, we measured nitric oxide production by cultured primary HUVECs and mouse macrophages (RAW264.7 cells) after exposure to these nanoparticles. Certain types of nanoparticles, particularly those composed of silica or metal, have been shown to affect the endothelial system, retarding cell growth, modifying endothelium-dependent vasodilation, and enhancing secretion of proinflammatory cytokines, apoptosis, and/or endothelial cell adhesion (see Supplementary Table).…”

“…[1][2][3] For this purpose, liposomes and solid lipid nanoparticles were functionalized with phosphatidic acid (PA-LIP and PA-SLN, respectively) or cardiolipin (CL-LIP), while PACA was decorated with poly-(ethylene glycol) chains (PEG-PACA). Testing of the biocompatibility of these nanoparticles in vitro is an essential step in order to anticipate and understand any problems which may arise during their in vivo administration, and some experiments in this direction have been already carried out.…”

Particle Targeting in Complex Biological Media

“…[164] Other examples are PEGylated polymeric particles, which have been reported to interact with the amyloid-beta (Aβ ) peptide in different environments. [165] The Aβ 1-42 peptide adsorption did not change the complement activation of particles nor the adsorption of other specific proteins, hence the safety and the clearance kinetics of the particles remained unchanged. [165] Brambilla et al suggested that these long-circulating particles had the potential to capture toxic forms of Aβ 1-42 peptides from systemic circulation as a treatment for Alzheimer's disease.…”

“…Recruiting Method Performance Albumin BSA Non-specific adsorption Improved stability of NPs [161] Specific adsorption Prevented NPs from being filtered by the reticuloendothelial system in vivo [162] HSA Non-specific adsorption Enhanced the accessibility of targeting ligands and targeting results of functionalized polymeric particles; improved stability of NPs [87,94] Apolipo-protein ApoE Specific adsorption Helped particles to cross the BBB and to deliver therapeutics to the brain [104a,163] ApoJ (clusterin) Specific adsorption Created stealth surface of PEG-or PEEP-coated NPs and reduced non-specific cellular uptake of these NPs [59,123b] ApoA4 Specific adsorption Decreased cellular uptake of NPs [93] ApoC3 RBP Specific adsorption Directed NPs to hepatic stellate cells [162] Vitronectin Specific adsorption Promoted efficient uptake of particles in cancer cells expressing high levels of vitronectin α ν β 3 integrin receptor [164] Aβ 1-42 peptide Specific adsorption Captured toxic forms of Aβ 1-42 peptides and improved Alzheimer's disease condition [165] a)…”

“…[165] Brambilla et al suggested that these long-circulating particles had the potential to capture toxic forms of Aβ 1-42 peptides from systemic circulation as a treatment for Alzheimer's disease. [165] …”