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Nanosized systems for efficient delivery of antitumoral and anti-inflammatory drugs
Get PDFThe purpose of the present PhD thesis was to study two different nanosized systems, liposomes and nanosuspensions. Liposomes were develop with the aim to improve the Triiodothyronine (T3) delivery to hepatic cancer cells and nanosuspensions were proposed to enhance dermal bioavailability of Diclofenac acid, a potent nonsteroidal anti-inflammatory drug (NSAID) with a very low aqueous solubility. T3, is a thyroid hormone normally synthesized and secreted by the thyroid gland and through interaction with its nuclear receptors (TRs) plays an essential role in morphogenesis and differentiation. However, there is increasing evidence for its role in hepatocellular carcinoma (HCC) suppression. Three different liposome systems, such as, conventional, Stealth (PEGylated) and Lf-modified-Stealth liposomes were successfully prepared, by the film hydration method, and characterized. Liposomes showed a mean diameter ranging between 86 and 126 nm and a PI lower than 0.28, as shown by PCS measurements. Liposomes cell interactions and cellular uptake were evaluated in three different HCC target cells (FaO, HepG2 and SKHep) by confocal microscopy using liposomes labeled with the lipophilic marker Rho-PE and loaded with the hydrophilic probe CF. Finally, in vitro cytotoxicity studies were carried out by using MTT assay to evaluate the toxicity of the liposome delivery system and to test the effect of T3 when incorporated into liposomes. These studies provides the great potential of liposomes as suitable carrier for T3 delivery to hepatoma cells. Internalization studies performed using Lf-modified-liposomes labeled with the lipophilic marker Rho-PE and loaded with the hydrophilic probe CF clearly demonstrated the effective internalization of both hydrophilic and lypophilic markers. Lf-liposome might markedly enhance the specific cell binding and cellular uptake in hepatoma cells due to the mediating of Lf that could bind to multiple receptors on cell surface such as ASGP-R with high affinity. From our data, emerges that liposome delivery system may insure a specific and sustained drug delivery, a reduced therapeutic dose and, in particular, should avoid deleterious side effects of T3 treatment. Overall, our results showed that liposomes are good candidates as liver delivery system of T3 since cell viability tests performed by using hepatoma cell lines demonstrated a very low toxicity of all three lyposome formulations. On the other hand, nanocrystal formulations, containing two different diclofenac acid crystal forms, were developed with the aim to improve dermal drug bioavailability. Nanosuspensions were obtaining using wet media milling technique and were characterized in terms of size distribution, morphology, zeta potential, differential scanning calorimetry and X-ray diffraction powder. The ability of the nanocrystals to improve dermal drug bioavailability was investigated in vitro using Franz diffusion vertical cells and newborn pig skin, in comparison with diclofenac acid coarse suspensions and a commercial topical formulation containing diclofenac sodium. Nanocrystals exhibited a mean diameter ranging between 279 and 315 nm and a PI lower than 0.25, as shown by PCS measurements. The XRDP and DSC analysis clearly indicated that the preparation process did not modify the diclofenac polymorphic forms. In vitro transdermal delivery experiments showed an improved skin deposition and permeation of the nanocrystals compared to coarse suspensions and diclofenac sodium commercial topical formulation. These results highlight the fundamental role of the crystal size on drug solubility and, thus, on the ability of a poorly soluble drug to cross the skin and accumulate in the deeper skin layers. Afterwards, the aims of the work were to develop Diclofenac acid (DCF) nanosuspensions obtained by the addition of a permeation enhancer, Transcutol (TRC), in the aqueous stabilizer solution and to study the effect of Transcutol on the transdermal permeation and skin accumulation of DCF nanocrystals. DCF-TRC-nanosuspensions, prepared using the wet media milling technique, were characterized in terms of size distribution, morphology, zeta potential, differential scanning calorimetry, X-ray diffraction powder and Fourier transform infrared spectroscopy.The influence of Transcutol concentration on skin penetration ability of DCF nanosuspensions was evaluated by in vitro skin penetration and permeation studies using Franz diffusion vertical cells and newborn pig skin, in comparison with DCF nanosuspension without TRC, DCF coarse suspension and a commercial topical formulation containing diclofenac sodium. Nanosuspensions with Transcutol exhibited a mean diameter of ∼350 nm and a polydispersity index ranging between 0.21 and 0.26, values greater than those of the nanosuspension without TRC. In vitro permeations studies showed that the increase of TRC in the nanosuspension formulations decreased the DCF skin delivery probably because the higher average diameter values of TRC nanosuspensions could decrease the DCF dissolution velocity with respect to nanosuspension without TRC. Moreover, although TRC is considered a powerful solubilizing agent, the increase of its concentration in the nanosuspension formulations determined the DCF solubility decrease. In light of these results, in the last part of this thesis nanocrystals of diclofenac (DCF) are proposed as a novel approach to treat skin inflammation, and their efficacy was validated in an animal model. Diffusion of DCF through mouse skin was investigated ex vivo, and the topical anti-inflammatory potential of the DCF nanosuspension was assessed in vivo by testing their activity against common inflammatory endpoints: inhibition of chemically induced oedema and leucocyte infiltration (reflected in myeloperoxidase–MPO-activity). TPA (12-O-tetradecanoylphorbol-13-acetate) is commonly used to induce inflammation in animal models. The therapeutic efficacy of the nanosuspension was
compared with those of a DCF coarse suspension and a commercial topical preparation containing diclofenac diethylamine, Voltaren Emulgel®. In vivo and ex vivo results have proven the superior anti-inflammatory efficacy of the nanocrystal suspension and its actual ability to localize the drug in the site of inflammation, compared to a commercial product (Voltaren). In conclusion, this study highlights the great potential of using nanocrystal suspensions as an effective strategy to improve topical bioavailability of poorly water-soluble drugs as well as a valid therapeutic approach
L’implicazione in C.I. Lewis. La nascita dell’implicazione stretta dagli scritti giovanili alla Symbolic Logic
Get PDFThe necessity of ordering the philosohpical path that leads Clarence
Irving Lewis to the formulation of the systems of strict implication
gives birth to this work of thesis. After a short general introduction
about the life and the philosophical view of Lewis, which is not
strictly related to the logical writings, the attention has been at first
focused on the historical-philosophic period between the nineteenth
and twentieth centuries the framework in which his logical studies
are put in, and afterwards on one of the first debates about material
implication which shows Bertrand Russell and Hugh MacColl
as leading actors. Subsequently an analysis of the early writings of
Lewis has been performed. This period started with Implication and
the Algebra of Logic, published in 1912, and ended in 1918 with Survey
of Symbolic Logic; and the subsequent revisions written in 1920
in the article A Strict Implication - An Emandation. For the first time,
the theory of the strict implication has been shown. Chapter three is
dedicated to the Symbolic Logic. This text is known as fundamental
in the history of Lewis’ thought. Particularly, the work has been interested
in a specific way to those chapters dedicated to truth-value
systems and to the notions of implication and deducibility, central
ideas in the Harvard’s philosopher logic system. Furthermore a section
has been dedicated to the analysis of the systems of strict implication:
S1, S2, S3, S4, S5, that represent the highest peak of the
Lewis’ logical study
Essays in labour and family economics
Get PDFAre the less healthy relatively less employed because they are unable to work? Or vice
versa? In the first part of the thesis, I evaluate the impact of health shocks on individual
labour market transitions in 27 EU countries and I explain these results through the
heterogeneity in social security systems across members. In the second part, I investigate
the mechanism through which tied transfers relate to both elderly and grandchildren
care later on in life
Razzismo quotidiano: la rappresentazione dello straniero nella stampa italiana (2000-2010)
Get PDFThe research involved the construction of a wide corpus of texts from five major national newspapers (Corriere della sera, la Repubblica, La Stampa, Il Giornale, Libero). The aim is to investigate the representation of migrants and of immigration in general on the Italian national press during the first decade of the XXI century. The main goal is to employ the means of critical discourse analysis to reflect on the social construction of prejudice about foreigners and on biased perceptions of the migratory process.
The analysis explores three major issues (migrants’ arrival by sea; immigration and crime; socio-economic struggle) which cover the most relevant areas of interest about the migratory phenomenon in Italy. The wide corpus (over 100 million words and more than 200 thousands articles) has been investigated through a combination of quantitative and qualitative methods. The intent is to offer a reliable and statistically significant linguistic analysis of the discursive strategies involved in the texts. The use of text analysis software helped to fulfill the goal of carrying out an analysis which employs modern methods, able to overcome and enrich previous investigations on the matter, based mostly on small and randomized samples or specific case studies.
The analysis of linguistic forms and structures primarily focused on referential and predicational strategies employed to describe social actors and on discursive strategies which reflect the fundamental cognitive structures (ideologies) underlying prejudice and struggle between social groups. The results confirmed the starting hypothesis and highlighted some of the most important discriminatory elements produced (or reproduced) by the media. The reader is often led to formulate biased and unrealistic opinions about the migratory phenomenon, therefore affecting social behaviour and intergroup relations
Biochemical, computer, and spectroscopic techniques applied to the study of prions and of combinations of antineoplastic drugs
Get PDFThis thesis collects the work I have done during the three-year PhD Course. The results obtained
are divided according to the research topics addressed:
· Drug discovery of anticancer agents and development of synergistic associations (Part I);
· Studies on the prion structure and the pathogenesis of prion diseases (Part II).
Studies referring to the Part I have been carried out at the University of Cagliari and were focalized
on the evaluation and experimental validation of the method known as Artificial Neural Network
(ANN), which allows to determine, and also to predict, types and degree of interaction of two or
more drugs in combination with one another(s). I have successfully applied the ANN approach to
combinations of two cytotoxic compounds, i.e. cis-platinum (CDDP), a potent antineoplastic used
in the therapy of some types of carcinoma, with Cu(II) complexes that were previously shown to
be endowed with potent cytotoxic activity in vitro (Pivetta et al., J Inorg Biochem. 2011 and 2012).
Binary combinations comprising CDDP and Cu(II) complexes revealed (Part I, Chapter I) a strong
synergistic cytotoxic effect against leukemia cell lines (Pivetta et al., Talanta 2013). The synergistic
effect was confirmed in CDDP-resistant leukemia and ovarian cancer cell lines (Part I, Chapter II).
Investigations on molecular bases of the CDDP – Cu(II) complexes synergism are in progress.
As for the Part II of my research, I firstly investigated the mechanisms underlying the process of
generation of pathogenic prion protein (PrPSc). These studies were carried out in part at the
University of Cagliari, and in part at the Rocky Mountains Laboratories (RML) of the NIAID/NIH in
USA (Hamilton, Montana), during my 14-month research internship as supplemental visiting fellow
in a graduate partnership program. The studies carried out in Cagliari have investigated 1H NMR
modifications of brain metabolite profiles in sheep from a Sardinian farm hit by natural Scrapie
with the aim to discriminate infected vs. Uninfected, and early vs. late phases of the prion
infection (Part II, Chapter I). The overall results, obtained by different chemometric tools, were
able to describe a metabolite profile of scrapie-infected sheep brain, with and without clinical sign,
different to that of healthy ones, and to suggest Ala as a biomarker of PrPSc deposition (Scano et
al., J Molecular Biosystem, 2015)
Studies conducted at the RML of NIAID/NIH have addressed the structural features of PrPSc in
order to identify regions of the protein involved in the process of misfolding (Part II, Chapter II). So
far, data suggest that i) the N-terminal portion of the prion protein may have a role in the
modulation of the protein aggregation process, typical of prion diseases, while ii) the central
portion seems capable to undergo aggregation into fibrils even in the absence of other regions of
the protein. However, further studies are needed to confirm the proposed role in
promoting/hindering the misfolding and subsequent aggregation process of the various protein
regions
Teorie dell’autorità e del potere nell’Islam sciita secondo l’opera di ʿAlī Fayyāḍ
Get PDFThe aim of this research is to investigate the work of ʿAlī Fayyāḍ, a prominent polit-ical and intellectual figure within Lebanese Hezbollah, and to analyse theoretical founda-tions of power and authority from a specific Shīʿa perspective. This will make it possible to reconstruct the nature of the relation between authority and religion, as well as its narration inside Hezbollah human environment, also with a view to comprehending the theory of po-litical authority through the study of the intellectual structure underpinning the religious au-thority. The intention is to go further the usual approaches of Security studies that all too often prevail in this research field
Educazione indigena in Perù. Il concetto di interculturalità e la sua applicazione nell’elaborazione del materiale didattico
Get PDFThe objective of this thesis is to analyse the transformation process of the indigenous oral literature in teaching materials within the scope of the bilingual intercultural education (BIE) in Perù. More specifically, the attention is focused on the experience of “Programa de Formación de Maestros Bilingües de la Amazonía Peruana” (FORMABIAP) that deals with the training of the bilingual teachers and the creation of curricula, methodologies and didactic materials, taking into consideration the cultural linguistic heritage of the students and the social reality in which they live. In the examined texts, which belong to the shawi and kukama cultures, it is evident that the persistence of a different measure in the orality as conscious stylistic choice is evident, and it aims at deconstructing schemes and structures that are typical of the western writing. The active participation of the indigenous students as writers, translators and in some cases as illustrators, removes the mediation of the western interpretative filter and facilitates the affirmation of “other” kinds of logic. The appropriation of the new Information and Communication Technologies (ICT) by the new autochthonous generations favours the expression of the performative character of the Amazonian culture and witnesses the reality of systems of thought different from the western one. The analysis of the current legislation and the different projects carried forward by the national policies, NGOs and religious missions, has allowed to outline a normative historical panorama in which the concept of interculturalism has assumed different meanings based on the political interests and its promoters. In recent times, despite being an instrument for cultural homologation and assimilation since the beginning, the school has undertaken an important role for the indigenous populations within the process of knowledge decolonization and the power relationships overrunning the national reality
Modelling in chimica computazionale: ottimizzazione di codici MD ed applicazioni allo studio di sistemi ad elevata carica
Get PDFM.DynaMix is a modular general purpose Molecular Dynamics code for simulations of arbitrary
mixtures of either rigid or flexible molecules. For its features and capabilities, M.DynaMix is
diffused in a large simulation community and it is worth to keep it efficient and updated.
With this goal in mind, a major revision of the package has been performed, leading to a version
where several enhancements have been added: two efficient grid-based algorithm for long range
interactions, SPME and ENUF, are now available; besides, a version of the code runnable on multi
graphics boards has been produced. With the new features, the program exhibits a remarkable
increase of computational efficiency and an improvement in global performance.
The new version of M.DynaMix has been applied for studying some selected high charged particle
system: DNA oligomers and ionic liquids. For oligomers, interactions between DNA and
counterions has been investigated, searching for sequence dependent features. For ionic liquids, we
focused on 1-decyl-3-methil-imidazolium chloride, to find a proper Force Field parameter set for its
description. In both cases, the problem of validation of MD simulations has been treated, testing a
new technique based upon the determination of quadrupolar decay parameters, for direct
comparison between simulation and experiments
Studio di complessi di rame (II) e platino (II) con proprietà antitumorali
Get PDFCisplatin is one of the most active drugs in anticancer therapy, and it is currently used
for the treatment of a wide range of cancers, in particular advanced ones. After its
introduction in clinical therapy, the research in this field has focused on the preparation
of new metal complexes with increased activity and lower side-effects. Besides, the use
of drug combinations with synergistic effect, i.e. an effect greater than the sum of the
effects of the single drugs, has been introduced. This thesis is focused on the preparation
of Cu(II) and Pt(II) complexes and on the study of their cytotoxic properties, alone or in
combination with cisplatin.
Cu(II) complexes with 1,10-phenantroline (phen), 1,10-phenantrolin-5,6-dione and 1,10-
phenantrolin-5,6-diol, with 1:1 or 1:2 metal:ligand stoichiometry, have been synthesized.
In addition, mixed Cu(II) complexes with phen and thiophene derivatives of general
formula [Cu(phen)2(T)](ClO4)2 (T=1-methylthio-thiophene-2-carboxylic acid, 2-
methylthio-thiophene-1-carboxylic acid, 2-thiophenecarboxamide, 2-
thiophenecarboxylate) have been prepared. A family of Pt(II) complexes of general
formula [Pt(P)(D)2](ClO4)2, being P a derivative of phen and D a derivative of
imidazolidin-2-thione, has been synthesized.
In order to find the species present in solution in conditions similar to the physiological
ones (37 °C and NaCl 0.1 M), the formation constants of the complexes have been
determined through potentiometric titrations. The dipole moments of the platinum
complexes have been determined through quantum mechanical calculations.
The in vitro cytotoxic activity of ligands and metal complexes has been evaluated against
a panel of human tumour cell lines, and it has been correlated to their structures.
Finally, a new method, based on experimental design and artificial neural networks, has
been proposed for the evaluation of the synergy in mixtures of two or more drugs.
Exploiting this method, the cytotoxic activity of mixture of cisplatin and three Cu(II)
complexes ([Cu(phen)(H2O)2(ClO4)2], [Cu(phen)2(H2O)](ClO4)2 e
[Cu(phen)2(imidazolidin-2-thione)](ClO4)2) has been studied, and the combination with
higher synergistic effect have been identified
Optimal generation scheduling for renewable microgrids using hydrogen storage systems
Get PDFThe topic of this thesis is the development of a tool for an optimal energy
management strategy (EMS) of the generators and energy storage systems
constituent microgrids, both grid-connected or isolated (stand-alone power
system) powered by Renewable Energy Sources (RES). In particular, a
novel control system is designed based on the resolution of the unit
commitment problem. For each time step, the proposed control system
compares the expected power produced by the renewable generators with
the expected load demand and determines the scheduling of the different
energy storage devices and generators for the next few hours, which
minimizes the operating cost of the overall microgrid. To take into account
for forecasting uncertainties, the generation of the different scenarios is
carried out through a discretization of the probability distribution function
of the forecasting errors for wind speed, solar radiation and load requests
by a set of finite states. A set of various scenarios are therefore analyzed
and compared by the control system to find the minimum operating costs.
The proposed algorithm is firstly applied to a microgrid at LABH2FER
(Sardegna Ricerche, Italy). Since the microgrid is under construction, the
expected performance is evaluated through a simulation modeling,
implemented in Matlab-Simulink. Furthermore, in order to highlight the
benefits of including weather forecasts and operating costs in the EMS, a
comparative analysis with a simpler EMS based on control states of storage
devices is carried out. The results of the comparative study demonstrate that
a reduction of almost 5-10% in the annual operating costs and energy losses
is achieved thanks to the implementation of the proposed control system.
Moreover, the proposed control strategy is implemented and tested to a
microgrid present at the University of Seville. Experimental results
demonstrate the feasibility and the actual functionality of the control
system. Additional benefits are also observed, such as the reduction in power exchanged with the upstream grid thanks to a better management of
the storage systems