Therapeutic potential of small interfering RNAs/micro interfering RNA in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and represents the third leading cause of cancer-related death worldwide. Current available therapeutic approaches are poorly effective, especially for the advanced forms of the disease. In the last year, short double stranded RNA molecules termed small interfering RNAs (siRNAs) and micro interfering RNAs (miRNA), emerged as interesting molecules with potential therapeutic value for HCC. The practical use of these molecules is however limited by the identification of optimal molecular targets and especially by the lack of effective and targeted HCC delivery systems. Here we focus our discussion on the most recent advances in the identification of siRNAs/ miRNAs molecular targets and on the development of suitable siRNA/miRNAs delivery systems

GT75 aptamer against eukaryotic elongation factor 1A as potential anticancer drug for castrate-resistant prostate cancer (CRPC).

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 cance

Recent advances in smart biotechnology: Hydrogels and nanocarriers for tailored bioactive molecules depot

Over the past ten years, the global biopharmaceutical market has remarkably grown, with ten over the top twenty worldwide high performance medical treatment sales being biologics. Thus, biotech R&D (research and development) sector is becoming a key leading branch, with expanding revenues. Biotechnology offers considerable advantages compared to traditional therapeutic approaches, such as reducing side effects, specific treatments, higher patient compliance and therefore more effective treatments leading to lower healthcare costs. Within this sector, smart nanotechnology and colloidal self-assembling systems represent pivotal tools able to modulate the delivery of therapeutics. A comprehensive understanding of the processes involved in the self assembly of the colloidal structures discussed therein is essential for the development of relevant biomedical applications. In this review we report the most promising and best performing platforms for specific classes of bioactive molecules and related target, spanning from siRNAs, gene/plasmids, proteins/growth factors, small synthetic therapeutics and bioimaging probes.Istituto Italiano di Tecnologia (IIT)COST Action [CA 15107]People Program (Marie Curie Actions) of the European Union's Seventh Framework Program under REA [606713 BIBAFOODS]Portuguese Foundation for Science and Technology (FCT) [PTDC/AGR-TEC/4814/2014, IF/01005/2014]Fundacao para a Ciencia e Tecnologia [SFRH/BPD/99982/2014]Danish National Research Foundation [DNRF 122]Villum Foundation [9301]Italian Ministry of Instruction, University and Research (MIUR), PRIN [20109PLMH2]"Fondazione Beneficentia Stiftung" VaduzFondo di Ateneo FRAFRAinfo:eu-repo/semantics/publishedVersio

Dissecting the role of the elongation factor 1A isoforms in hepatocellular carcinoma cells by liposome-mediated delivery of siRNAs

Eukaryotic elongation factor 1A (eEF1A), a protein involved in protein synthesis, has two major isoforms, eEF1A1 and eEF1A2. Despite the evidences of their involvement in hepatocellular carcinoma (HCC), the quantitative contribution of each of the two isoforms to the disease is unknown. We depleted the two isoforms by means of siRNAs and studied the effects in three different HCC cell lines. Particular care was dedicated to select siRNAs able to target each of the two isoform without affecting the other one. This is not a trivial aspect due to the high sequence homology between eEF1A1 and eEF1A2. The selected siRNAs can specifically deplete either eEF1A1 or eEF1A2. This, in turn, results in an impairment of cell vitality, growth and arrest in the G1/G0 phase of the cell cycle. Notably, these effects are quantitatively superior following eEF1A1 than eEF1A2 depletion. Moreover, functional tests revealed that the G1/G0 block induced by eEF1A1 depletion depends on the down-regulation of the transcription factor E2F1, a known player in HCC. In conclusion, our data indicate that the independent targeting of the two eEF1A isoforms is effective in reducing HCC cell growth and that eEF1A1 depletion may result in a more evident effect

Simultaneous Release and ADME Processes of Poorly Water-Soluble Drugs: Mathematical Modeling

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolismexcretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior

Potential applications of nanocellulose-containing materials in the biomedical field

Because of its high biocompatibility, bio-degradability, low-cost and easy availability, cellulose finds application in disparate areas of research. Here we focus our attention on the most recent and attractive potential applications of cellulose in the biomedical field. We first describe the chemical/structural composition of cellulose fibers, the cellulose sources/features and cellulose chemical modifications employed to improve its properties. We then move to the description of cellulose potential applications in biomedicine. In this field, cellulose is most considered in recent research in the form of nano-sized particle, i.e., nanofiber cellulose (NFC) or cellulose nanocrystal (CNC). NFC is obtained from cellulose via chemical and mechanical methods. CNC can be obtained from macroscopic or microscopic forms of cellulose following strong acid hydrolysis. NFC and CNC are used for several reasons including the mechanical properties, the extended surface area and the low toxicity. Here we present some potential applications of nano-sized cellulose in the fields of wound healing, bone-cartilage regeneration, dental application and different human diseases including cancer. To witness the close proximity of nano-sized cellulose to the practical biomedical use, examples of recent clinical trials are also reported. Altogether, the described examples strongly support the enormous application potential of nano-sized cellulose in the biomedical field

Uso sinergico della reologia e della risonanza magnetica nucleare a basso campo per caratterizzare l’espettorato di pazienti con fibrosi cistica

Hyper-concentrated and more viscous mucus presents in the lungs of patients suffering from cystic fibrosis (CF) provoke mucus stasis providing an optimal environment for bacterial growth. The sputum of CF patients has been subjected to rheological and low-field NMR investigation, providing information on i) the state of viscoelasticity (G0, h 0 ) and mucus hydration (T2avg), ii) possible correlations also with parameter of patients clinical status given by spirometry(FEV1) iii) the structure of the polymeric network in mucus. The absence of correlation among magnetic and mechanical-rheological relaxation notes that these phenomena are linked to different aspects of sputum. However, correlations exist among FEV1, T2av and rheological properties G0, h 0. Moreover, T2avg correlates with the mucociliary clearability index (MCI) and cough clearability index (CCI), two indices derived from the rheological characterization. The clinical condition of the patient can, therefore, be summarized by T2avg alone. Finally, information from the two characterizations make it possible to estimate the mesh size distribution of the polymeric network pervading sputum. This knowledge is very useful to better understand drugs penetration in mucus

Hydrogel mesh size evaluation

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

Epigenetic and miRNAs dysregulation in prostate cancer: the role of nutraceuticals.

6noThe control of cancer onset and progression is recognized to benefit from specific molecular targeting. MiRNAs are increasingly being implicated in prostate cancer, and the evidence suggests they are possible targets for molecular therapy and diagnosis. In cancer cells, growing attention has been dedicated to novel molecular mechanisms linking the epigenetic scenario to miRNA dysregulation. Currently, the rising evidence shows that nutritional and natural agents, the so-called nutraceuticals, could modulate miRNAs expression, and, as a consequence, might influence cellular responses in health or diseases conditions, including cancer. Among dietary components, plant-derived polyphenols are receiving wide interest, either for their anti-aging and anti-oxidant properties, or for their more general "cell-protective" effects. Above all, their role in preventing the occurrence/recurrence of cancer and, in particular, their potentiality in nutritional intervention for modulating the functions of miRNAs and the epigenetic mechanisms, is still under active debate. This review is focused on the more recent highlights of the impact of miRNAs dysregulation on the onset and progression of prostate cancer, their interplay with epigenetic control and their modulation by natural agents.reservedmixedBosutti, Alessandra; Dapas, Barbara; Grassi, Gabriele; Passamonti, Sabina; Zanconati, Fabrizio; Scaggiante, BrunaBosutti, Alessandra; Dapas, Barbara; Grassi, Gabriele; Passamonti, Sabina; Zanconati, Fabrizio; Scaggiante, Brun

Rapid and cost-effective xenograft hepatocellular carcinoma model in Zebrafish for drug testing

We developed a novel, rapid and cost-effective Zebrafish xenograft model of hepatocellular carcinoma(HCC) for drug screening in the disease. Following injection into the yolk sack of Zebrafish larvae of the human HCC cell line JHH6 stained by a vital dye, tumor mass growth was followed by fluorescence microscopy and by human Ki67 quantification. Tumor induced neo-angiogenesis was evaluated by alkaline phosphatase staining of the vessels, by using the Tg(fli1:EGFP)y1 strain of Zebrafish and by the quantification of the zebrafish vascular endothelial growth factor and of its receptor. We show that it is feasible to micro-inject JHH6 in Zebrafish larvae, that injected cells can grow for different days and that this induces a marked neo-angiogenesis. Finally, we show that our model allows testing the effects of anti-HCC drugs such as Bortezomib. Compared to more complex HCC mouse models, our model is far less expensive, faster to set up and does not need immunosuppressant treatment. Finally, the model makes use of JHH6, an aggressive form of HCC cell line never tested before in Zebrafish. In conclusion, the possibility to test anti HCC/neo-angiogenesis drugs makes our JHH6 model useful to select therapeutic molecules for a highly vascularized umor such as HCC