Lipid-based nanoparticles with high binding affinity for amyloid-beta1-42 peptide.
The neurotoxic beta-amyloid peptide (Abeta), formed in anomalous amounts in Alzheimer's disease (AD), is released as monomer and then undergoes aggregation forming oligomers, fibrils and plaques in diseased brains. Abeta aggregates are considered as possible targets for therapy and/or diagnosis of AD. Since nanoparticles (NPs) are promising vehicles for imaging probes and therapeutic agents, we realized and characterized two types of NPs (liposomes and solid lipid nanoparticles, 145 and 76 nm average size, respectively) functionalized to target Abeta(1-42) with high affinity. Preliminary immunostaining studies identified anionic phospholipids [phosphatidic acid (PA) and cardiolipin (CL)] as suitable Abeta(1-42) ligands. PA/CL-functionalized, but not plain, NPs interacted with Abeta(1-42) aggregates as indicated by ultracentrifugation experiments, in which binding reaction occurred in solution, and by Surface Plasmon Resonance (SPR) experiments, in which NPs flowed onto immobilized Abeta(1-42). All these experiments were carried out in buffered saline. SPR studies indicated that, when exposed on NPs surface, PA/CL display very high affinity for Abeta(1-42) fibrils (22-60 nm), likely because of the occurrence of multivalent interactions which markedly decrease the dissociation of PA/CL NPs from Abeta. Noteworthy, PA/CL NPs did not bind to bovine serum albumin. The PA/CL NPs described in this work are endowed with the highest affinity for Abeta so far reported. These characteristics make our NPs a very promising vector for the targeted delivery of potential new diagnostic and therapeutic molecules to be tested in appropriate animal models.
Gobbi
Marco
M
Department of Biochemistry and Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Re
Francesca
F
Canovi
Mara
M
Beeg
Marten
M
Gregori
Maria
M
Sesana
Silvia
S
Sonnino
Sandro
S
Brogioli
Doriano
D
Musicanti
Claudia
C
Gasco
Paolo
P
Salmona
Mario
M
Masserini
Massimo E
ME
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D014461:Ultracentrifugation
D016229:Amyloid beta-Peptides; D008055:Lipids; D008081:Liposomes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)