Drug development for neurodegenerative diseases such as Alzheimer's disease (AD) is a challenge, not only due to the cellular molecular mechanisms involved, but also because of the inherent ...difficulty of most molecules to cross the blood-brain-barrier (BBB). A promising approach to overcome these drawbacks is developing fluorinated molecules and supramolecular assemblies. This review focuses on the therapeutic potential of new fluorinated molecules, developed as active and selective agents for AD, to meet the desired pharmacokinetic/pharmacodynamic properties and BBB targeting. The methods to fluorinate organic molecules and a brief characterization of the mechanisms of AD progression and therapeutic approaches are described. The paradigm of cell biology knowledge and fluorine biochemistry such as, organofluorine inhibitors of amyloid fibrilogenesis, is highlighted.
A novel system to carry and protect epigallocatechin gallate (EGCG), an antioxidant from the green tea, is reported. The system consists of maltodextrin and gum arabic nanoparticles coated with ...egg-yolk
l-α-phosphatidylcholine (Egg-PC)/stearylamine (SA) bilayers. In this study, the polysaccharide core was produced by homogenization followed by spray-drying. The lipid coating was performed by the lipid film hydration method. The polysaccharide core revealed negative zeta potential, which changed to opposite signs after lipid coating. The presence of lipid layers was evidenced by cryogenic-transmission (cryo-TEM) and scanning (cryo-SEM) electron microscopy studies. An increase in size was observed after lipid coating as determined by dynamic light scattering (DLS). Atomic force microscopy (AFM) demonstrated that the polysaccharide core provides high resistance to mechanical strength. The lipid/particle assemblies show high retention efficiency of EGCG at physiological pH, opening the possibility of their use for delivery and controlled release of tea catechins.
The amyloid-β peptide (Aβ) is a major fibrillar component of neuritic plaques in Alzheimer's disease brains and is related to the pathogenesis of the disease. Soluble oligomers that precede fibril ...formation have been proposed as the main neurotoxic species that contributes to neurodegeneration and dementia. We hypothesize that oligomerization and cytotoxicity can be repressed by nanoparticles (NPs) that induce conformational changes in Aβ42. We show here that fluorinated and hydrogenated NPs with different abilities to change Aβ42 conformation influence oligomerization as assessed by atomic force microscopy, immunoblot and SDS-PAGE. Fluorinated NPs, which promote an increase in α-helical content, exert an antioligomeric effect, whereas hydrogenated analogues do not and lead to aggregation. Cytotoxicity assays confirmed our hypothesis by indicating that the conformational conversion of Aβ42 into an α-helical-enriched secondary structure also has antiapoptotic activity, thereby increasing the viability of cells treated with oligomeric species.
The amyloid‐β peptide (Aβ) plays a central role in the mechanism of Alzheimer's disease, being the main constituent of the plaque deposits found in AD brains. Aβ amyloid formation and deposition are ...due to a conformational switching to a β‐enriched secondary structure. Our strategy to inhibit Aβ aggregation involves the re‐conversion of Aβ conformation by adsorption to nanoparticles. NPs were synthesized by sulfonation and sulfation of polystyrene, leading to microgels and latexes. Both polymeric nanostructures affect the conformation of Aβ inducing an unordered state. Oligomerization was delayed and cytotoxicity reduced. The proper balance between hydrophilic moieties and hydrophobic chains seems to be an essential feature of effective NPs.
Sulfonated and sulfated polystyrene nanoparticles interact with Aβ peptide inducing randomization of its structure. As a consequence, the oligomerization process is disturbed and the peptide induced toxicity to neuroblastoma cells is reduced. These results comprise attractive achievements for the development of approaches for the study and therapy of protein misfolding diseases.
The present study was designed to test the cellular uptake of PEGylated liposomes targeted to transferrin receptor and to α-synuclein by a cell model of the blood-brain barrier (BBB).
PEGylated ...immunoliposomes were prepared with anti-transferrin receptor OX26 and anti-α-synuclein LB509 antibodies to overcome the BBB in Parkinson's disease.
The doubly targeted immunoliposomes bind to transferrin receptor and to α-synuclein protein, as assessed by ELISA assays. We establish that 40% of an encapsulated tested drug (epigallocatechin-3-gallate) is released in a time frame of 44 h, which is reasonable for sustained release. The cellular uptake of doubly targeted immunoliposomes in cultured brain endothelial cells hCMEC/D3 was two-times more efficient than that of PEGylated liposomes.
Immunoliposomes targeted to BBB receptors and to α-synuclein could potentially enable the transport of drugs across the BBB and reach one of the drug targets in Parkinson's disease.
The adsorption and assembly of B18 peptide on various solid surfaces were studied by reflectometry techniques and atomic force microscopy. B18 is the minimal membrane binding and fusogenic motif of ...the sea urchin protein bindin, which mediates the fertilization process. Silicon substrates were modified to obtain hydrophilic charged surfaces (oxide layer and polyelectrolyte multilayers) and hydrophobic surfaces (octadecyltrichlorosilane). B18 does not adsorb on hydrophilic positively charged surfaces, which was attributed to electrostatic repulsion since the peptide is positively charged. In contrast, the peptide irreversibly adsorbs on negatively charged hydrophilic as well as on hydrophobic surfaces. B18 showed higher affinity for hydrophobic surfaces than for hydrophilic negatively charged surfaces, which must be due to the presence of hydrophobic side chains at both ends of the molecule. Atomic force microscopy provided the indication that lateral diffusion on the surface affects the adsorption process of B18 on hydrophobic surfaces. The adsorption of the peptide on negatively charged surfaces was characterized by the formation of globular clusters.
Refolding the sheets. Fluorinated nanoparticles with a diameter of 4 nm were found to induce α‐helix‐rich structures in the fibril‐forming peptide, B18. In contrast, the alkylated analogues induced ...aggregation and β‐sheet formation (see CD spectra). Fluorinated particles are proposed to be potential candidates for the stabilization of protein monomeric structures.
Colloidal gold nanoparticles intensify the anticancer response of the drug bortezomib, a proteasome inhibitor. Polyethylene glycol-coated gold nanoparticles and the drug show a synergistic effect in ...reducing the cell viability of prostate cancer cell line Du145. It was observed a significant cell viability reduction with bortezomib concentrations as low as 4 nM. The proteasome inhibitor alone had to be present at concentrations in the ranger of 120 nM to induce identical cytotoxicity response. These findings demonstrate that gold nanoparticles enhancing the permeation and retention (EPR) effect in Du145 cells and open the possibility to decrease multi-drug resistance (MDR). The in vitro results of functionalized gold nanoparticles, internalized by cancer cells, pave the way for a more efficient proteasome inhibitor delivery and release in adenocarcinoma cells.
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