The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been ...suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.
Resveratrol (RES) is a natural polyphenolic non-flavonoid compound present in grapes, mulberries, peanuts, rhubarb and in several other plants. Numerous health effects have been related with its ...intake, such as anti-carcinogenic, anti-inflammatory and brain protective effects. The neuroprotective effects of RES in neurological diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases, are related to the protection of neurons against oxidative damage and toxicity, and to the prevention of apoptotic neuronal death. In brain cancer, RES induces cell apoptotic death and inhibits angiogenesis and tumor invasion. Despite its great potential as therapeutic agent for the treatment of several diseases, RES exhibits some limitations. It has poor water solubility and it is chemically instable, being degraded by isomerization once exposed to high temperatures, pH changes, UV light, or certain types of enzymes. Thus, RES has low bioavailability, limiting its biological and pharmacological benefits. To overcome these limitations, RES can be delivered by nanocarriers. This field of nanomedicine studies how the drug administration, pharmacokinetics, and pharmacodynamics are affected by the use of nanosized materials. The role of nanotechnology, in the prevention and treatment of neurological diseases, arises from the necessity to mask the physicochemical properties of therapeutic drugs to prolong the half-life and to be able to cross the blood-brain barrier (BBB). This can be achieved by encapsulating the drug in a nanoparticle (NP), which can be made of different kinds of materials. An increasing trend to encapsulate and direct RES to the brain has been observed. RES has been encapsulated in many different types of nanosystems, as liposomes, lipid and polymeric NPs. Furthermore, some of these nanocarriers have been modified with targeting molecules able to recognize the brain areas. Then, this article aims to overview the RES benefits and limitations in the treatment of neurological diseases, as the different nanotechnology strategies to overcome these limitations.
Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their ...specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.
Alzheimer's disease (AD) is an incurable neurological illness and the leading cause of dementia, characterized by amyloid β (Aβ) fibril deposits. Caffeic acid (CA) has demonstrated potential value ...for AD therapy due to its anti-amyloidogenic, anti-inflammatory, and antioxidant properties. However, its chemical instability and limited bioavailability limit its therapeutic potential in vivo. Herein, liposomes loading CA were produced by distinct techniques. Taking advantage of the overexpression of transferrin (Tf) receptors in brain endothelial cells, Tf was conjugated to the liposomes’ surface to direct the CA-loaded nanoparticles (NPs) to the blood-brain barrier (BBB). The optimized Tf-modified NPs exhibited a mean size of around 140 nm, a polydispersity index lower than 0.2, and a neutral surface charge, being appropriate for drug delivery. The Tf-functionalized liposomes showed suitable encapsulation efficiency and physical stability for at least 2 months. Furthermore, in simulated physiological settings, the NPs ensured the sustained release of CA for 8 days. The anti-amyloidogenic efficacy of the optimized drug delivery system (DDS) was investigated. The data show that CA-loaded Tf-functionalized liposomes are capable of preventing Aβ aggregation and fibril formation, and disaggregating mature fibrils. Hence, the proposed brain-targeted DDS may be a potential strategy for preventing and treating AD. Future studies in animal models of AD will be valuable to validate the therapeutic efficacy of the optimized nanosystem.
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•Liposomes containing caffeic acid (CA) were produced by various techniques.•Liposomes’ surface was modified with transferrin for improved targeting ability.•Nanoparticles exhibited appropriate physicochemical properties for drug delivery.•CA-loaded liposomes inhibited the aggregation of amyloid β (Aβ) peptides.•CA-loaded liposomes disaggregated mature Aβ fibrils.
Alzheimer's disease (AD) is a serious health concern, affecting millions of people globally, which leads to cognitive impairment, dementia, and inevitable death. There is still no medically accepted ...treatment for AD. Developing therapeutic treatments for AD is an overwhelming challenge in the medicinal field, as the exact mechanics underlying its devastating symptoms is still not completely understood. Rather than the unknown mechanism of the disease, one of the limiting factors in developing new drugs for AD is the blood-brain barrier (BBB). A combination of nanotechnology with fluorinated molecules is proposed as a promising therapeutic treatment to meet the desired pharmacokinetic/physiochemical properties for crossing the BBB passage. This paper reviews the research conducted on fluorine-containing compounds and fluorinated nanoparticles (NPs) that have been designed and tested for the inhibition of amyloid-beta (Aβ) peptide aggregation. Additionally, this study summarizes fluorinated molecules and NPs as promising agents and further future work is encouraged to be effective for the treatment of AD.
Clinically available medications face several hurdles that limit their therapeutic activity, including restricted access to the target tissues due to biological barriers, low bioavailability, and ...poor pharmacokinetic properties. Drug delivery systems (DDS), such as nanoparticles (NPs) and hydrogels, have been widely employed to address these issues. Furthermore, the DDS improves drugs' therapeutic efficacy while reducing undesired side effects caused by the unspecific distribution over the different tissues. The integration of NPs into hydrogels has emerged to improve their performance when compared with each DDS individually. The combination of both DDS enhances the ability to deliver drugs in a localized and targeted manner, paired with a controlled and sustained drug release, resulting in increased drug therapeutic effectiveness. With the incorporation of the NPs into hydrogels, it is possible to apply the DDS locally and then provide a sustained release of the NPs in the site of action, allowing the drug uptake in the required location. Additionally, most of the materials used to produce the hydrogels and NPs present low toxicity. This article provides a systematic review of the polymeric NPs-loaded hydrogels developed for various biomedical applications, focusing on studies that present in vivo data.
Aggregation of α-synuclein has been recognized as a critical event in the pathogenesis of Parkinson's disease whose prevalence is increasing with great socio-economic challenges for future ...generations. Here, we developed a sensitive and specific electrochemical immunosensor for the detection and quantification of this biomarker, based on the voltammetric study of a redox indicator signal, which decreases upon the analyte recognition by the antibody due to the electronic resistance increase. The proposed immunosensor is based on a screen-printed carbon electrode modified in a layer-by-layer approach, which through extensive characterization led to the successful nanostructuration of the transducer, through the drop-cast of 3.0 μL of a 0.1 mg mL−1 single-walled carbon nanotubes suspension followed by electrodeposition of gold nanoparticles in a 3 mM HAuCl4 solution under a −0.2 V potential for 150 s. Monoclonal antibodies were immobilized on the gold nanoparticles surface through chemical modification at an optimal concentration of 200 μg mL−1. Using the proposed immunosensor, α-synuclein was detected in the range of 0.01–10 ng mL−1 with a 4.1 and 12.6 pg mL−1 limits of detection and quantification, respectively. Recovery values of 96.7, 106.2 and 102.9% were attained for the tested concentrations spiked in fetal bovine serum while also presenting excellent specificity and stability throughout one month. The nanostructured immunosensor provided a great interface for electronic transduction and biological recognition events, which enabled fast, sensitive and specific detection of α-synuclein while being based on a simple and inexpensive technology requiring small sample volumes, crucial characteristics for application in point-of-care testing.
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•A simple and effective label-free procedure was developed for α-synuclein detection.•The immunosensor is based on a nanostructured screen-printed carbon electrode.•Nanostructuration of the immunosensor amplified its electrochemical behavior.•Detection and quantification limits of 4.1 and 12.6 pg mL−1 were attained.•The immunosensor enables highly sensitive and specific detection of α-synuclein.
Amyloidosis, commonly known as amyloid-associated diseases, is characterized by improperly folded proteins accumulating in tissues and eventually causing organ damage, which is linked to several ...disorders ranging from neurodegenerative to peripheral diseases. It has an enormous societal and financial impact on the global health sector. Due to the complexity of protein misfolding and intertwined aggregation, there are no effective disease-modifying medications at present, and the condition is likely mis/non-diagnosed half of the time. Nonetheless, over the last two decades, substantial research into aggregation processes has revealed the possibilities of new intervention approaches. On the other hand, fluorine has been a rising star in therapeutic development for numerous neurodegenerative illnesses and other peripheral diseases. In this study, we revised and emphasized the possible significance of fluorine-modified therapeutic molecules and fluorine-modified nanoparticles (NPs) in the modulation of amyloidogenic proteins, including insulin, amyloid beta peptide (Aβ), prion protein (PrP), transthyretin (TTR) and Huntingtin (htt).
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•Amyloidosis is characterized by improperly folded proteins accumulating in tissues.•There are no effective amyloidosis-modifying medications.•Florine could modulate amyloidogenic proteins aggregation.
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•Immuno nanoparticles enhance the BBB permeability for encapsulated peptides.•The cellular uptake of PLGA immuno nanoparticles corroborates a saturation mechanism.•PLGA nanoparticles ...show a high efficiency to entrap the peptide iAβ5.•In vitro assays show an enhanced concentration of targeted carriers into the cells.
During the last few decades, relevant efforts have been reported to design nanocarriers for drug transport through the blood brain barrier (BBB). New drugs, such as peptide iAβ5, capable to inhibit the aggregates associated with Alzheimeŕs disease (AD) are being tested but the most frequent drawback is to reach the brain in the desired concentrations due to the low BBB permeability-surface area. Our approach, as a proof of concept to improve drug transport through the BBB, is based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles with surface functionalized with anti-transferrin receptor monoclonal antibody (OX26) and anti-Aβ (DE2B4) to deliver encapsulated iAβ5 into the brain. Porcine brain capillary endothelial cells (PBCECs) were used as a BBB model to evaluate the system efficacy and toxicity. The uptake of immune nanoparticles with a controlled delivery of the peptide iAβ5 was substantially increased compared to the nanoparticles (NPs) without monoclonal antibody functionalization.
Polymeric nanoparticles (NPs), utilized extensively in biomedical applications, have received increasing interest in the preceding years and today represent an established part of the nanotechnology ...field ....
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