Characterizing the Effect of Multivalent Conjugates Composed of Aβ-Specific Ligands and Metal Nanoparticles on Neurotoxic Fibrillar Aggregation
Source abstract
Abstract
Therapeutically active small molecules represent promising nonimmunogenic alternatives to antibodies for specifically targeting disease-relevant receptors. However, a potential drawback compared to antibody-antigen interactions may be the lower affinity of small molecules toward receptors. Here, we overcome this low-affinity problem by coating the surface of nanoparticles (NPs) with multiple ligands. Specifically, we explored the use of gold and platinum nanoparticles to increase the binding affinity of Aβ-specific small molecules to inhibit Aβ peptide aggregation into fibrils in vitro. The interactions of bare NPs, free ligands, and NP-bound ligands with Aβ are comprehensively studied via physicochemical methods (spectroscopy, microscopy, immunologic tests) and cell assays. Reduction of thioflavin T fluorescence, as an indicator for β-sheet content, and inhibition of cellular Aβ excretion are even more effective with NP-bound ligands than with the free ligands. The results from this study may have implications in the development of therapeutics for treating Alzheimer's disease.
Source: openalex_inverted_index · Quality: baseline
Research context
OpenAlex topics: Alzheimer's disease research and treatments · Nanocluster Synthesis and Applications · Nanoparticle-Based Drug Delivery
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Technical Chemistry I and Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, 45141 Essen, Germany
Institute for Organic Chemistry, University of Duisburg-Essen, 45117 Essen, Germany
Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Chemical Biology, Zentrum für Medizinische Biotechnologie (ZMB), Fakultät für Biologie, Universtität Duisburg-Essen, 45117 Essen, Germany
Department Neuropathology, University of Düsseldorf Medical School, 40225 Düsseldorf, Germany
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich, 52425 Jülich, Germany
Bionanotechnology, Zentrum für Medizinische Biotechnologie (ZMB), Fakultät für Biologie, University of Duisburg-Essen, 45117 Essen, Germany
Funding
Helmholtz Association · Evonik Industries AG · Medizinische Fakultät, Heinrich-Heine-Universität Düsseldorf · Fakultät für Chemie, Universität Duisburg-Essen
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63. aTypically, the last fraction contained a significant amount of very large aggregates, when AuNPs were present, which became detectable only after denaturation with 6 M guanidine hydrochloride and heating to 100 °C (fraction 23 inFigures4b andS22). Due to the high density of AuNPs, the particles will sediment under the applied DGC conditions. It is thus assumed that all species of Aβ (independent of their size and shape) will—when adsorbed on AuNPs—be detected only in the last fraction after denaturation.
64. bAs shown in theSupporting Information(Figure S21), the linear range of quantitative Aβ detection is limited with ELISA, meaning that the antibody did not detect the whole amount of Aβ, but was already saturated with Aβ in some fractions. Thus one has to consider that the black reference line (Aβ control) would appear much higher and the measured inhibitory effects may be much larger.
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