Selegiline-functionalized, PEGylated poly(alkyl cyanoacrylate) nanoparticles: Investigation of interaction with amyloid-β peptide and surface reorganization.
Alzheimer's disease (AD) is a neurodegenerative disorder for which the research of new treatments is highly challenging. Since the fibrillogenesis of amyloid-β peptide 1-42 (Aβ(1-42)) peptide is considered as a major cause of neuronal degeneration, specific interest has been focused on aromatic molecules for targeting this peptide. In this paper, the synthesis of selegiline-functionalized and fluorescent poly(alkyl cyanoacrylate) nanoparticles (NPs) and their evaluation for the targeting of the Aβ(1-42) peptide are reported. The synthetic strategy relied on the design of amphiphilic copolymers by tandem Knoevenagel-Michael addition of cyanoacetate derivatives, followed by their self-assembly in aqueous solutions to give the corresponding NPs. Different cyanoacetates were used: (i) hexadecyl cyanoacetate (HDCA) to form the hydrophobic core of the NPs; (ii) rhodamine B cyanoacetate (RCA) for fluorescent purposes; (iii) methoxypoly(ethylene glycol) cyanoacetate (MePEGCA) for stealth properties and (iv) selegiline-poly(ethylene glycol) cyanoacetate (SelPEGCA) to obtain the desired functionality. Two different amphiphilic copolymers were synthesized, a selegiline-containing copolymer, P(MePEGCA-co-SelPEGCA-co-HDCA), and a rhodamine-labelled counterpart, P(MePEGCA-co-RCA-co-HDCA), further blended at variable ratios to tune the amount of selegiline moieties displayed at the surface of the NPs. Optimal formulations involving the different amphiphilic copolymers were determined by the study of the NP colloidal characteristics. Interestingly, it was shown that the zeta potential value of the selegiline-functionalized nanoparticles dramatically decreased, thus emphasizing a significant modification in the surface charge of the nanoparticles. Capillary electrophoresis has then been used to test the ability of the selegiline-functionalized NPs to interact with the Aβ(1-42) peptide. In comparison with non functionalized NPs, no increase of the interaction between these functionalized NPs and the monomeric form of the Aβ(1-42) peptide was observed, thus highlighting the lack of availability of the ligand at the surface of the nanoparticles. A mechanism explaining this result has been proposed and was mainly based on the burial of the hydrophobic selegiline ligand within the nanoparticles core.
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, Univ. Paris-Sud 11, UMR CNRS 8612, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Benjamin
B
Le Droumaguet
Hayfa
H
Souguir
Davide
D
Brambilla
Romain
R
Verpillot
Julien
J
Nicolas
Myriam
M
Taverna
Patrick
P
Couvreur
Karine
K
Andrieux
D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003102:Colloids; D003487:Cyanoacrylates / Q000737:chemistry*; D016503:Drug Delivery Systems; D015195:Drug Design; D019075:Electrophoresis, Capillary; D057927:Hydrophobic and Hydrophilic Interactions; D053758:Nanoparticles; D010446:Peptide Fragments / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012235:Rhodamines / Q000737:chemistry; D012642:Selegiline / Q000008:administration & dosage / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D003102:Colloids; D003487:Cyanoacrylates; D010446:Peptide Fragments; D012235:Rhodamines; C075222:amyloid beta-protein (1-42); D012642:Selegiline; D011092:Polyethylene Glycols