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.
The present study takes advantage of the beneficial effects of resveratrol as a neuroprotective compound. Resveratrol-loaded solid lipid nanoparticles were functionalized with apolipoprotein E which ...can be recognized by the LDL receptors overexpressed on the blood-brain barrier.
Transmission electron microscopy images revealed spherical nanoparticles, dynamic light scattering gave a Z-average lower than 200 nm, and a zeta potential of around -13 mV and very high resveratrol entrapment efficiency (ca. 90 %). In vitro cytotoxic effects were assessed by MTT and LDH assays in hCMEC/D3 cell line and revealed no toxicity up to 50 μM over 4 h of incubation. The permeability through hCMEC/D3 monolayers showed a significant increase (1.8-fold higher) for resveratrol-loaded solid lipid nanoparticles functionalized with apolipoprotein E when compared to non-functionalized ones.
In conclusion, these nanosystems might be a promising strategy for resveratrol delivery into the brain, while protecting it from degradation in the blood stream. Graphical abstract .
Several strategies have been implemented to enhance brain drug delivery, and herein solid lipid nanoparticles functionalized with apolipoprotein E were tested in hCMEC/D3 cell monolayers. The mean ...diameter of 160 nm, negative charge of -12 mV, and their lipophilic characteristics make these nanosystems suitable for brain delivery. Confocal images and flow cytometry data showed a cellular uptake increase of 1.8-fold for SLN-Palmitate-ApoE and 1.9-fold for SLN-DSPE-ApoE when compared with the non-functionalized SLNs. Clathrin-mediated endocytosis was distinguished as the preferential internalization pathway involved in cellular uptake and nanoparticles could cross the blood-brain barrier predominantly by a transcellular pathway. The understanding of the mechanisms involved in the transport of these nanosystems through the blood-brain barrier may potentiate their application on brain drug delivery.
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Oral administration is the preferred route for drug delivery and nanosystems represent a promising tool for protection and transport of hardly soluble, chemically unstable and poorly ...permeable drugs through the intestinal barrier.
In the present work, we have studied lipid nanoparticles cellular uptake, internalization pathways and transcytosis routes through Caco-2 cell monolayers.
Both lipid nanosystems presented similar size (∼180nm) and surface charge (−30mV). Nanostructured lipid carriers showed a higher cellular uptake and permeability across the barrier, but solid lipid nanoparticles could enter cells faster than the former. The internalization of lipid nanoparticles occurs mainly through a clathrin-mediated endocytosis mechanism, although caveolae-mediated endocytosis is also involved in the uptake.
Both lipid nanoparticles were able to cross the intestinal barrier by a preferential transcellular route. This work contributed to a better knowledge of the developed nanosystems for the oral delivery of a wide spectrum of drugs.
Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid ...nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between −10 mV and −15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml−1 over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier.
Resveratrol is a polyphenolic compound produced by a wide variety of plants. This compound has interesting functions namely as antioxidant, anti-inflammatory, anticarcinogenic, cell cycle inhibitor, ...anti-aging, cardioprotector, neuroprotector, obesity and diabetes preventive. The purpose of this study is to take advantage of the beneficial effects of resveratrol as a neuroprotector reducing the risk of neurodegenerative disorders, especially Alzheimer's disease and Parkinson's disease and reducing the risk of brain cancer due to its antioxidant, anti-inflammatory and anticarcinogenic activity. However the blood-brain barrier represents a considerable obstacle to brain entry of the majority of drugs and thus severely restricts the therapy of many serious central nervous system diseases.Furthermore, the pharmacokinetic properties of resveratrol are not favorable to its free administration, since the compound has poor bioavailability, low water solubility, and is chemically unstable.Therefore the aim is to develop a specific functionalized drug delivery system that protects resveratrol during its transit inside the organism until it reaches the target preserving its pharmacological properties and protecting from degradation and, at the same time, directing this drug to brain where it can exercise its neuroprotective effects.Solid lipid nanoparticles(SLNs) loaded with resveratrol were produced and successfully functionalized with ApoE since apolipoprotein E is sufficient to mediate the transport of NPs into the brain.The formulations were completely characterizedto evaluate the quality of the developed resveratrol-loaded nanoparticles for targeted brain drug delivery.TEM images revealed that these formulations produce two populations of nanoparticles, one that stands out clearly and is characterized by having a size well below (<150 nm), and other, less pronounced, but with a greater diameter (~200 nm).Anaverage resveratrol entrapment efficiency over 90% was obtained for both SLNs with ApoE using DSPE or palmitate. Dynamic light scattering measurements gave a Z-average of ~ 170 nm in the case of DSPE and a Z-average of ~ 200 nm in the case of palmitate with a PI of <0.2, and a reasonable negative zeta potential of around −13 mV. These characteristics remained unchanged for at least 1 month. The release studies showed that the system is capable of providing a controlled and prolonged release of resveratrol with small losses of drug until it reaches its target (the brain).Functionalization of SLNs with ApoE was clearly demonstrated through fluorometric assays and evaluating the infrared spectra (using FTIR) for both types of functionalization performed.The results suggest that the functionalization of SLNs with ApoE resulted in dynamic stable systems capable of being used as controlled-release models for targeting brain delivery of resveratrol. Both functionalized nanodelivery systems (DSPE mediated and palmitate mediated) can be considered suitable carriers for resveratrol, conferring protection to this drug, targeting to the brain and allowing a controlled release after achieve the therapeutic target.
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