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Soft nanocarrier development as a versatile approach to brain delivery and targeting
Get PDFThe blood–brain barrier (BBB) is a selective system of endothelial cells, joined through the tight junctions, that protect and maintain the homeostasis of the Central Nervous System (CNS). Only small molecule or drugs, with high lipid solubility and a lower molecular mass under 400–500 Da, can cross the BBB in pharmacologically significant amounts, limiting the uptake of most therapeutic agents into the brain.
Currently, the management of neurological with aggressive and invasive techniques (surgery, see Appendix 3), achieves higher therapeutic effect compared to conventional delivery methods, such as systemic administration via intravenous injection or oral administration. However invasive techniques achieve less compliance.
This has led to the development of vogue treatments such as nose-to-brain technologies (see Appendix 2), FUS-induced BBB opening, fusion protein chaperones, stem cells, gene therapy, use of natural compounds and neuroprotectants, in order to increase the neuroavailability of various advanced drug delivery systems. These strategies provide promising alternatives that are able to ameliorate the treatment of brain disease.
At this purpose, several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, liposomes, niosomes and micelles to the newer systems, e.g. nanoemulsions, micro and nano-bubbles, nanosuspensions and nanogels, have been studied for the delivery of therapeutics to CNS. Many of the proposed nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical
success for the management of CNS conditions such as brain tumours, HIV encephalopathy, neurodegenerative disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity.
Targeted drug delivery is a means of concentrating drugs at a specific site relative to other parts of the body. It spares the rest of the body from toxic effects of the drug and it is also a potential means of improving therapeutic index.
This Ph.D. thesis focused on the study of the formulation of different nanocarriers for brain delivery
by two different administration routes: (1) Focused Ultrasound-mediated drug delivery, a technique that offer a unique non-invasive avenue to deliver drugs to the brain through transient opening of the BBB by using of ultrasound in combination with gas-filled bubbles. Our laboratory developed new carriers, the “Bubblesomes”®, able to combine the characteristics of a drug carrier and a contrast agent (theranostic system). When focused ultrasound is applied in presence of drug loaded nanobubbles intravenously administered, inertial cavitation is induced, due to the rapid expansion and violent collapsing of bubbles. This can cause the temporal and fully reversible opening of BBB due to the enhanced endothelial porosity and vascular permeability phenomenon called sonoporation, resulting in an increased drug uptake.
(2) Intranasal drug delivery, a non-invasive route to reach directly the brain, circumvent the BBB, from the nose along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain
Biosensors & enzymatic fuel cells based on direct electron transfer of dehydrogenases: characterization and applications
Get PDFIl lavoro svolto durante i tre anni di dottorato è stato indirizzato verso lo sviluppo di nuovi metodi di sintesi ed elettrosintesi di nanomateriali metallici o carboniosi per il miglioramento del trasferimento elettronico diretto tra l’enzima e l’elettrodo. Questo miglioramento si traduce in un notevole incremento della sensibilità, stabilità e selettività dei biosensori sviluppati nonché della potenza generata da una pila enzimatica a biocombustibile, (Biofuel Cell). La prima parte della tesi riguarda lo studio e l’ottimizzazione del trasferimento elettronico diretto della cellobiosio deidrogenasi (CDH), un enzima appartenente alle flavoemeossidoreduttasi, costituito da due subunità dotate rispettivamente di cofattore FAD (subunità I) e heme b (subunità II). In questa parte abbiamo sintetizzato nanoparticelle di oro e di argento con un nuovo metodo “green”, che impiega come
agente riducente la quercetina, un noto flavonoide presente in numerosi alimenti e bevande (es. tè, capperi, mirtilli, etc.). La reazione è stata condotta a temperatura ambiente e a pressione atmosferica senza ulteriore purificazione in quanto la quercetina
è nota avere un comportamento stabilizzante delle sospensioni colloidali. Le suddette nanoparticelle sono state impiegate nella costruzione di biosensori per la determinazione del lattosio e di una pila a biocombustibile glucosio/ossigeno.
Successivamente, abbiamo sviluppato un nuovo metodo per l’elettrodeposizione di nanoparticelle di oro in modo da ottenere una superficie nanostrutturata ordinata che ha portato allo sviluppo di un biosensore per la determinazione del glucosio nella saliva.
La seconda parte della tesi riguarda lo studio del meccanismo del trasferimento elettronico diretto della fruttosio deidrogenasi (FDH), con particolare attenzione rivolta all’influenza dei cationi monovalenti e bivalenti, all’influenza della forma delle
nanoparticelle sulla catalisi enzimatica, all’individuazione dei siti “heme” coinvolti nel trasferimento elettronico diretto attraverso l’accesso ad una porzione idrofobica dell’enzima, ed infine allo sviluppo di un biosensore per la determinazione del fruttosio
realizzato immobilizzando la FDH su elettrodi di oro altamente poroso.The aim of this thesis is the study and the enhancement of the direct electron transfer of two different dehydrogenases, by means of a proper nanostructuration of the electrodes, for biosensors and enzymatic fuel cells (EFCs) development. Cellobiose dehydrogenase (CDH) is an extracellular enzyme belonging to the oxidoreductase group. CDH contains two subunits: (a) subunit I is the dehydrogenase domain (DHCDH), similar to the domain of other oxidoreductases, which belongs to the glucose-methanol-choline (GMC) oxidoreductase superfamily with a flavin adenine dinucleotide (FAD) co-factor covalently bound to the enzyme structure; (b) subunit II is the cytochrome domain (CYTCDH), which contains a heme b and acts as a built-in mediator by shuttling the electrons to a modified electrode. Both subunits are connected through a flexible linker responsible of the modulation of the internal electron transfer (IET) rate by varying the experimental conditions, such as changes of pH and divalent cations the concentration. Fructose dehydrogenase (FDH) is a membrane-bound flavocytochrome oxidoreductase which also belongs to the hemoflavoproteins family. FDH is a heterotrimeric membrane-bound enzyme complex with a molecular mass of 146.4 kDa,
consisting of three subunits: (a) subunit I (DHFDH) is the catalytic domain with a covalently bound flavin adenine dinucleotide (FAD) cofactor, where D-(-)-fructose is involved in a 2H+/2e- oxidation to 5-dehydro-D-(-)-fructose; (b) subunit II (CYTFDH) acts as a built-in electron acceptor with three heme c moieties covalently bound to the enzyme scaffold and two of them involved in the electron transfer pathway; (c) subunit III is not involved in the electron transfer but plays a key role for the enzyme complex stability.
The central target of the present thesis is the possibility to improve the electron transfer through the electrode nanostructuration, which can be realized by exploiting new nanomaterials as well as new nanostructuration methods (e.g. “green” synthesized metal nanoparticles, electrodeposition etc.). In the thesis much attention has been paid also to the understanding of the electron transfer pathway of FDH, which would be of fundamental interest in the near future for the development of highly sensitive biosensors and efficient EFCs. The biosensors realized and optimized in this thesis are prototypes of devices that, hopefully, will be commercially available on the market in the next future
Synergistic immunopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts
No full textEchinacea purpurea (L.) Moench extracts are used in the production of standardized herbal medicines for the prevention and treatment of upper respiratory infections. Unsaturated N-alkylamide lipids, the main constituents of E. purpurea and E. angustifolia preparations capable of activating the cannabinoid receptor type-2 (CB2) have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles. Here we show that ethanolic E. purpurea radix and herba extracts produce synergistic pharmacological effects on the endocannabinoid system in vitro. Superadditive action of N-alkylamide combinations were seen at the level of intracellular calcium release as a function of CB2 receptor activation. Likewise, synergism of the radix and herba tinctures was observed in experiments measuring LPS-stimulated cytokine expression from human PBMCs. While the expression of the anti-inflammatory cytokine IL-10 was significantly superstimulated, the expression of the pro-inflammatory TNF-alpha protein was inhibited more strongly upon combination of the extracts. We show that N-alkylamides act in concert and exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport and degradation
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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