ABSTRACT
Introduction: The development of new materials and tools for radiology is key to the implementation of this diagnostic technique in clinics. In this work, we evaluated the differential accumulation of peptide-functionalized GNRs in a transgenic animal model (APPswe/PSENd1E9) of Alzheimer's disease (AD) by computed tomography (CT) and measured the pharmacokinetic parameters and bioaccumulation of the nanosystem. Methods: The GNRs were functionalized with two peptides, Ang2 and D1, which conferred on them the properties of crossing the blood-brain barrier and binding to amyloid aggregates, respectively, thus making them a diagnostic tool with great potential for AD. The nanosystem was administered intravenously in APPswe/PSEN1dE9 model mice of 4-, 8- and 18-months of age, and the accumulation of gold nanoparticles was observed by computed tomography (CT). The gold accumulation and biodistribution were determined by atomic absorption. Results: Our findings indicated that 18-month-old animals treated with our nanosystem (GNR-D1/Ang2) displayed noticeable differences in CT signals compared to those treated with a control nanosystem (GNR-Ang2). However, no such distinctions were observed in younger animals. This suggests that our nanosystem holds the potential to effectively detect AD pathology. Discussion: These results support the future development of gold nanoparticle-based technology as a more effective and accessible alternative for the diagnosis of AD and represent a significant advance in the development of gold nanoparticle applications in disease diagnosis.
Subject(s)
Alzheimer Disease , Metal Nanoparticles , Nanotubes , Mice , Animals , Gold/chemistry , Bioaccumulation , Tissue Distribution , Metal Nanoparticles/chemistry , Peptides/chemistry , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Amyloid/metabolism , Tomography, X-Ray Computed , Nanotubes/chemistry , Tomography , Amyloid beta-Peptides/metabolism , Mice, Transgenic , Disease Models, Animal , Brain/metabolismABSTRACT
The ß-amyloid (Aß) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of Aß species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of Aß in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of Aß aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of Aß using NIR probes in vivo.
Subject(s)
Alzheimer Disease , Metal Nanoparticles , Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/metabolism , Animals , Caenorhabditis elegans , Fluorescent Dyes/chemistry , Gold , Metal Nanoparticles/chemistry , MiceABSTRACT
The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the Aß peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.
Subject(s)
Alzheimer Disease , Nanotubes , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Gold , Mice , Mice, Transgenic , X-Ray MicrotomographyABSTRACT
Alzheimer's disease (AD), considered a common type of dementia, is mainly characterized by a progressive loss of memory and cognitive functions. Although its cause is multifactorial, it has been associated with the accumulation of toxic aggregates of the amyloid-ß peptide (Aß) and neurofibrillary tangles (NFTs) of tau protein. At present, the development of highly sensitive, high cost-effective, and non-invasive diagnostic tools for AD remains a challenge. In the last decades, nanomaterials have emerged as an interesting and useful tool in nanomedicine for diagnostics and therapy. In particular, plasmonic nanoparticles are well-known to display unique optical properties derived from their localized surface plasmon resonance (LSPR), allowing their use as transducers in various sensing configurations and enhancing detection sensitivity. Herein, this review focuses on current advances in in vitro sensing techniques such as Surface-enhanced Raman scattering (SERS), Surface-enhanced fluorescence (SEF), colorimetric, and LSPR using plasmonic nanoparticles for improving the sensitivity in the detection of main biomarkers related to AD in body fluids. Additionally, we refer to the use of plasmonic nanoparticles for in vivo imaging studies in AD.
Subject(s)
Alzheimer Disease , Metal Nanoparticles , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Humans , Spectrum Analysis, Raman , Surface Plasmon ResonanceABSTRACT
The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.
