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Introduzione I tumori cutanei sono la forma di cancro più diffusa nel mondo e rappresentano un problema di salute pubblica perché sono in continua crescita. Le forme più comuni di tumori cutanei sono epiteliomi (90-95%), melanomi (5%) seguiti da neoplasie rare della pelle (1%). Gli epiteliomi sono tumori non melanocitici, più frequenti e meno aggressivi del melanoma che si originano dai cheratinociti e sono distinti in carcinoma delle cellule basali (o basalioma) e carcinoma spinocellulare (detto anche spinalioma o carcinoma squamocellulare). Abbiamo poi il melanoma, tumore che si origina dai melanociti, meno frequente ma più aggressivo dei primi due (Goyal et al., 2020). Dal punto di vista terapeutico i tumori non melanomi vengono trattati, nella maggior parte dei casi, con rimozione chirurgica (Ho e Argaez, 2019). Il melanoma necessita di valutazioni approfondite per il grado di invasività e molto spesso la rimozione chirurgica deve essere accompagnata da eventuali terapie farmacologiche. In particolare, sono a disposizione varie terapie: a bersaglio molecolare, immunoterapia (Malas et al., 2014) e chemioterapia. Spesso però generano resistenza e nel tempo perdono di efficacia. Il presente lavoro ha l’obiettivo di studiare i meccanismi fenotipici e molecolari di alcuni composti nutraceutici per i quali il gruppo di lavoro ha evidenze aneddotiche di attività antitumorale in vivo dopo applicazione cutanea. Obbiettivi 1) Indagare i meccanismi molecolari dell’attività «antitumorale anedottica» di una formulazione galenica dimostrandola almeno in vitro . 2) Estendere lo screening ad altre molecole «nutraceutiche» riconosciute come sicure dal punto di vista tossicologico che in letteratura abbiano dimostrato una potenziale attività antineoplastica. 3) Ottimizzazione delle caratteristiche chimico-fisiche degli attivi selezionati e validati, per ottenere attivi ottimizzati (multicomposti a migliorata solubilità), con analisi della solubilità e rilascio. 4) Elaborare un algoritmo matematico per il confronto degli effetti dei diversi attivi, in forma nativa ed ottimizzata. 5) Studiare le componenti della matrice veicolante per incorporare gli attivi ottimizzati.

Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD) and particularly small interfering RNAs (siRNAs), are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC), a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work.

For Hepatocellular carcinoma (HCC) there are no effective treatments thus, the individuation of novel therapeutic approaches and molecular targets are necessary. Small interference RNAs (siRNAs) are small double stranded RNAs able to induce gene silencing and thus represent a potential innovative therapeutic tool. The main impediment in using siRNAs is their high degradation rate in the biological environment. To protect siRNAs, we developed a novel delivery system based on the polymer (α,β-poly-(N-2-hydroxyethyl)-D,L-aspartamide-PHEA) derivatized with diethylene triamine (DETA) linked via a polyethylene glycol (PEG) to galactose (GAL) molecules (PDPG). The GAL residue has been introduced to target the Asialo-glycoprotein receptor (ASGPR), overexpressed in HCC cells.

Background. Chronic lymphocytic leukaemia (CLL), the most common form of leukaemia in adults in Western countries, is characterized by the clonal expansion of B cells. Despite major advances in CLL therapy/diagnosis, the medical approach to CLL can be further improved. Here we explore the potential diagnostic/therapeutic role of the elongation factor 1 A (eEF1A) in CLL. Two major isoforms of eEF1A proteins exist: the ubiquitous eEF1A1 and the tissue-specialized eEF1A2. Beside their role in the elongation step of translation, both isoforms are involved in different cellular processes such as cell proliferation and apoptosis. Whereas both eEF1A isoforms play a role in solid and hematologic human tumors, nothing is known in CLL. Methods. eEF1A1/eEF1A2 amounts were quantitated by quantitative real time PCR and western blotting in the lymphocytes of 46 CLL patients vs 26 normal control. eEF1A1 functional role in CLL was investigated in a cellular (MEC-1) and in a subcutaneous xenograft animal model of CLL via its targeting by an aptamer (GT75) or a siRNA (siA1), we previously developed. As control molecules an inactive aptamer (CT75) or siRNA (siGL2) were used. Results. At the mRNA level, eEF1A1 but not eEF1A2 was significantly (p=0,0081) more elevated in CLL lymphocytes compared to control. At the protein level, both eEF1A1 and eEF1A2 were more elevated (p=0,028) in CLL lymphocytes compared to control. Moreover, eEF1A1 but not eEF1A2 protein levels were higher (p=0,0042) in patient which died during the study compared to those surviving. Finally, eEF1A1 targeting by either GT75 or siA1 resulted in MEC-1 viability down regulation (p=0,04) mostly due to autophagy stimulation. In vivo, GT75 or siA1 resulted in tumor growth down-regulation (p=0.014) and extension of animal survival (p=0.014), demonstrating the functional role of eEF1A1 in CLL. Conclusions. The increase of eEF1A1/eEF1A2 protein in lymphocytes of CLL patient cells suggests a role as possible novel CLL markers. The increase of eEF1A1 protein in dead vs surviving patients may confer to eEF1A1 also the role of a novel prognostic marker. This, together with the involvement of eEF1A1 in MEC-1 survival in vitro and in vivo, opens the possibility to consider eEF1A1 also as a novel therapeutic target in CLL.

This paper deals with the role of the two isoforms of the eukaryotic elongation factor 1A on hepatocellular carcinoma

This paper deals with the effect of aptamers on hepatocellular carcinoma

The increase of long surviving cystic fibrosis (CF) patients needs great effort for the assessment of lung functionality/inflammation since the majority of them still die of respiratory failure. The commonly used test (forced expiratory volume in the first second (FEV1), evaluation of inflammatory markers such as blood neutrophil counts (BNC) and acute-phase reactants such as C-reactive protein (CRP)) can be complex in their execution (FEV1) or expensive (BNC, CRP). Thus, in consideration of the intense monitoring required in CF patients, more effective, low cost and simple strategies are urgently necessary. As it is well known [1, 2] that the sputum of patients affected by CF or other obstructive pulmonary diseases contain pathological concentrations of proteins, alginates, DNA, bacteria and mucin, it is conceivable that these components can affect the magnetic relaxation of the water hydrogens entrapped in the sputum as it occurs in aqueous polymeric solutions and gels [3]. As the illness severity is connected to the concentration of these components, Low field NMR could represent a profitable tool to evaluate lung functionality/inflammation. Indeed, measuring the average sputum spin-spin relaxation time T2m of both artificial sputum samples (water added by different amounts of the pathological components), and conditional sputum (healthy volunteers saliva, added by different amounts of the pathological components), we found that T2m is greatly affected by the presence of pathological components when their concentration ranges from normal up to pathological concentrations. In addition, we found a good statistical correlation between T2m - FEV1, T2m - CRP and T2m -BNC. Figure 1 shows the decrease of T2m relative to a CF patient in comparison with healthy subjects and patients affected by less severe lung pathological conditions, i.e. asthma and chronic obstructive pulmonary disease (COPD). In conclusion, we can affirm that Low field NMR has the potential to become a valuable, fast and economic monitoring tool for pulmonary diseases in CF patients, as well as in other chronic pulmonary diseases.

This chapter is aimed to illustrate and to discuss membrane applications in the delivery field focussing the attention on the mechanisms ruling mass transport. Accordingly, membranes physical characteristics such as intrinsic topological structure, viscoelastic nature and membrane-drug interaction are considered. In this frame the continuity equation is presented and particularised in relation to different scenarios such as polymeric matrices, osmotic systems and electrotransport. On the basis of this theoretical frame, some examples of mathematical models serving to get drug diffusion coefficient by means of data fitting are shown. In particular, it is stressed the necessity of experimentally match the assumptions on which interpretative models relay. Among the great variety of membrane applications in the delivery field, those related to the oral and transdermal administration route are presented and discussed. Consequently, coating processes, asymmetric membranes and membranes devoted to colon delivery are presented for what concerns oral delivery systems. Membranes for passive diffusion delivery systems and physically enhanced delivery systems constitute the topic of transdermal administration route. The final part of this chapter is devoted to some membranes applications in the nano-medicine field. In particular, the restenosis prevention and the bioavailability enhancement due to nano-crystals will be dealt with

The importance of hydrogels in the biomedical and biotechnological fields induced researchers to experimentally and theoretically study their properties. Among them, one of the most important is represented by the mesh size distribution of their polymeric network. Indeed, this characteristic heavily rules the mass exchange processes between the hydrogel and the surrounding. The aim of this chapter is to present and discuss some techniques devoted to the estimation of the polymeric network mesh size. In particular, attention will be focused on rheology, low-field NMR, crioporosimetry, and release tests

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is a global health problem representing the sixth most common cancer and the third cause of cancer related death worldwide. The number of deaths per year in HCC is comparable to the incidence number, underlying the aggressive behavior of HCC and the modest efficacy of available curative treatments. Effective HCC treatment is problematic also due to the lack of early and specific diagnostic markers. In this regard, particular interest has been put on the tyrosine kinase with Ig and EGF homology domains 2 (TIE2), a receptor of angiopoietins, predominantly present on endothelial cells but also observed on monocytes (TIE-2-expressing monocytes – TEMs). Recently, a work by Matsubara et al showed that the amount of circulating TEMs is higher in HCV/HCC patients compared to HCV patients or healthy subjects. Additionally the authors showed that TEMs have a diagnostic potential for HCC. Whereas the molecular mechanisms responsible for this observation remain elusive and further studies are necessary to confirm this finding, the work of Matsubara et al may contribute to the identification of a novel HCC prognostic and diagnostic marker.

Prostate cancer diagnosis is increasing, being the second most frequently cancer in men worldwide. The treatment of castrate-resistant prostate cancer is often unsuccessfully and new therapeutic interventions are searching for. Nucleic acid aptamers targeting eEF1A proteins are emerging molecular tools for the control of cancer growth. We found that an aptamer named GT75 was able to bind to eEF1A proteins of human prostate cancer cell lines and to significantly and specifically reduce their growth with respect to the control oligomer CT75. The highest anti-proliferation effect was found in the androgen-independent PC-3 cells. Interestingly, GT75 was able to specifically inhibit the migration of PC-3 cells but not that of the nontumorigenic PZHPV-7 cells. The overall results suggest that the GT75 aptamer targeting eEF1A proteins is a promising molecular drug to develop for the control of the castrate-resistant prostate cancer.