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.
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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.
The search for talent is pervasive in youth sports. Selection/exclusion in many sports follows a maturity-related gradient largely during the interval of puberty and growth spurt. As such, there is ...emphasis on methods for assessing maturation. Commonly used methods for assessing status (skeletal age, secondary sex characteristics) and estimating timing (ages at peak height velocity (PHV) and menarche) in youth athletes and two relatively recent anthropometric (non-invasive) methods (status-percentage of predicted near adult height attained at observation, timing-predicted maturity offset/age at PHV) are described and evaluated. The latter methods need further validation with athletes. Currently available data on the maturity status and timing of youth athletes are subsequently summarised. Selection for sport and potential maturity-related correlates are then discussed in the context of talent development and associated models. Talent development from novice to elite is superimposed on a constantly changing base-the processes of physical growth, biological maturation and behavioural development, which occur simultaneously and interact with each other. The processes which are highly individualised also interact with the demands of a sport per se and with involved adults (coaches, trainers, administrators, parents/guardians).
In the present paper, we report results from a study of the structure and physicochemical properties of gold nanoparticles modified with poly(ethylene glycol) (PEG) designed for the drug delivery of ...the proteasome inhibitor Bortezomib (BTZ) in cancer therapy. A number of advanced analytical techniques were used to define important physicochemical characteristics such as composition, structure, surface properties, particle size and morphology. A new approach based on detailed NMR studies was employed to define specific intermolecular interactions and mechanisms of drug immobilization and location into surface modified gold nanoparticles (AuNPs). Particularly important information was gained from analysis of NMR spectroscopic parameters such as the spectral line shape, translation diffusion, the nuclear Overhauser effect (NOE) and spin-lattice relaxation (T1). The results confirmed the coexistence of two different types of BTZ inclusion into polyethylene glycol coated gold nanoparticles: (i) association with the polymer chains by weak H-bonds and/or dipole-charge interactions and (ii) adsorption on the surface of the gold nanoparticles. The results allowed for determination of the overall structure of Bortezomib loaded PEG coated AuNPs, which is related to the therapeutic drug efficacy and activity in the treatment of cancer.
Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor, and the clinically available approaches for its treatment are not curative. Despite the intensive research, biological ...barriers such as the blood-brain barrier (BBB) and tumor cell membranes are major obstacles to developing novel effective therapies. Nanoparticles (NPs) have been explored as drug delivery systems (DDS) to improve GBM therapeutic strategies. NPs can circumvent many of the biological barriers posed by this devastating disease, enhancing drug accumulation in the target site. This can be achieved by employing strategies to target the transferrin receptor (TfR), which is heavily distributed in BBB and GBM cells. These targeting strategies comprise the modification of NPs' surface with various molecules, such as transferrin (Tf), antibodies, and targeting peptides. This review provides an overview and discussion on the recent advances concerning the strategies to target the TfR in the treatment of GBM, as their benefits and limitations.
The purpose of this study was to determine intra- and inter-observer agreement for the three skeletal ages derived from the TW2 method among male pubertal soccer players. The sample included 142 ...participants aged 11.0–15.3 years. Films of the left hand-wrist were evaluated twice by each of two observers. Twenty bones were rated and three scoring systems used to determine SA adopting the TW2 version: 20-bone, CARPAL and RUS. Overall agreement rates were 95.1% and 93.8% for, respectively, Observer A and Observer B. Although, agreement rates between observers differed for 13 bones (5 carpals, metacarpal-I, metacarpal-III, metacarpal-V, proximal phalanges-I, III and V, distal phalanx-III), intra-class correlationa were as follows: 0.990 (20-bone), 0.969 (CARPAL), and 0.988 (RUS). For the three SA protocols, BIAS was negligible: 0.02 years (20-bone), 0.04 years (CARPAL), and 0.03 years (RUS). Observer-associated error was not significant for 20-bone SA (TEM = 0.25 years, %CV = 1.86) neither RUS SA (TEM = 0.31 years, %CV = 2.22). Although the mean difference for CARPAL SAs between observers (observer A: 12.48±1.18 years; observer B: 12.29±1.24 years; t = 4.662, p<0.01), the inter-observer disagreement had little impact (TEM: 0.34 years: %CV: 2.78). The concordance between bone-specific developmental stages seemed was somewhat more problematic for the carpals than for the long bones. Finally, when error due to the observer is not greater than one stage and the replicated assignments had equal probability for being lower or higher compared to initial assignments, the effect on SAs was trivial or small.
Liposomes modified with anti-amyloid (19B8) and anti-transferrin receptor (OX26) monoclonal antibodies through the coupling reagents maleimide and biotin-streptavidin system.
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...•Immunoliposomes for peptide delivery to brain areas affected by amyloid are proposed.•The cellular uptake depends on the cross linker used for liposome surface decoration.•Bulky ligands between the liposome surface and antibody are more efficient.•In vivo assays show an enhanced concentration of the targeted carriers in rat brains.
Drug delivery systems that can reach brain areas affected by amyloid deposits are still underdeveloped. We propose pegylated liposomes functionalized with two antibodies, the anti-transferrin receptor monoclonal antibody (OX26MAb) and the anti-amyloid beta peptide antibody (19B8MAb), as nanocarriers of drugs for Alzheimer’s disease therapy. Two distinct conjugation methods are investigated. In one formulation, the OX26MAb is conjugated to the tip of polyethylene glycol molecules through the maleimide group and the 19B8MAb is bound through the streptavidin–biotin complex. In the second system the conjugation reagents are swapped between the antibodies. Fluorescence spectroscopy experiments on porcine brain capillary endothelial cells show that the cellular uptake of the immunoliposomes is substantially more efficient if OX26MAb antibody is conjugated through the streptavidin–biotin complex instead of the maleimide group. The ability of the immunoliposomes to cross the blood brain barrier was established by in vivo studies in wild type rats. Our results demonstrate the importance of the conjugation method used to bind the antibody that targets the blood brain barrier to immunoliposomes for efficient drug delivery to the brain.
Digital distribution is a new technology that is revolutionizing the pop-rock music market. Extensive debate exists on the long tail theory that predicts a niche strategy in the pop-rock market ...versus the conventional wisdom of a “superstar effect” that predicts skewness in the market outcomes for artists. Our research tests the empirical evidence of such effects and elaborates on how the firms respond to this disruptive technological revolution and how this response changes strategic management.
•The pop-rock music market is facing a disruptive technological change.•There is empirical evidence of the persistence of the superstar effect.•Digital music and live music guide the strategic management in the market.
A drug delivery system based on colloidal pegylated gold nanoparticles (PEGAuNPs) conjugated with the tyrosine kinase inhibitor afatinib was designed and tested for enhancing the drug activity ...against pancreatic and NSCLC cells.
PEGAuNPs were synthesized and characterized physicochemically. Confocal imaging was performed to evaluate the nanoparticle (NP) internalization in cancer cells. For cell-cycle distribution analysis, conjugated NPs and afatinib alone were incubated with cells and alterations on the cell-cycle profile subsequently analyzed by total DNA staining. Cancer cell survival and growth inhibition following incubation with afatinib and PEGAuNPs-afatinib (concentrations between 0.007 and 0.500 µM afatinib) were evaluated.
A higher cellular uptake of PEGAuNPs was observed by cancer cells. Our data suggest an efficient conjugation of PEGAuNPs with the drug, enhancing the afatinib activity in comparison with afatinib alone. In fact, IC50 and GI50 results obtained show that the PEGAuNPs-afatinib conjugate is ca. 5 and 20 times more potent than afatinib alone in S2-013 and A549 cell lines, respectively.
Conjugating PEGAuNPs with afatinib is a promising antitumor delivery system for cancer therapy as it improves drug efficacy, allowing a reduction in drug dose used and minimizing possible toxicity-related side effects.
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