PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation: toward engineering of functional nanomedicines for Alzheimer's disease.
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".
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Univ Paris-Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Chatenay-Malabry, France.
Davide
D
Brambilla
Romain
R
Verpillot
Benjamin
B
Le Droumaguet
Julien
J
Nicolas
Myriam
M
Taverna
Juraj
J
Kóňa
Barbara
B
Lettiero
S Hossein
SH
Hashemi
Line
L
De Kimpe
Mara
M
Canovi
Marco
M
Gobbi
Valérie
V
Nicolas
Wiep
W
Scheper
S Moein
SM
Moghimi
Igor
I
Tvaroška
Patrick
P
Couvreur
Karine
K
Andrieux
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D052160:Benzothiazoles; D057005:Bioengineering; D003167:Complement Activation; D019075:Electrophoresis, Capillary; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols; D011485:Protein Binding; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D011092:Polyethylene Glycols