Publications

Abstract One of the earliest synthetic antimalarial drugs, quinacrine, was recently reported as interesting for the treatment of acute myeloid leukemia. Inspired by this and similar findings, we evaluated a set of quinacrine analogues against gastric (MKN28), colon (Caco-2), and breast (MFC-7) cancer cell lines and one normal human fibroblast cell line (HFF-1). All the compounds, previously developed by us as dual-stage antimalarial leads, displayed antiproliferative activity, and one of the set stood out as selective toward the gastric cancer cell line, MKN-28. Interestingly, this compound was transported across an in vitro MKN-28 model cell line in low amounts, and approximately 80% was trapped inside those cells. Nuclear targeting of the same compound and its interactions with calf thymus DNA were assessed through combined fluorescence microscopy, spectroscopy, and calorimetry studies, which provided evidence for the compound's ability to reach the nucleus and to interact with DNA.

Abstract An immobilization scheme, via glycidyloxypropyl-trimethoxysilane sol-gel crosslinking, of chondroitin sulfate (CS) or fucoidan (Fd), inspired by the biological silicate bridge found in CS, is presented here. It revealed to constitute a simple and effective way of producing biopolymer-silicate composites without compromising the carboxylate- and sulfate- groups of the biopolymers, those which play a determinant role in the binding to metal cations. In the case of the Fd composite, the immobilization process resulted in the similar to 4-fold enhancement of the negatively charged sorption sites, probably due to unfolding effects induced by the synthesis conditions. Textural analysis of the composites showed a microporous, low surface area (6-12 m(2)/g), microstructure which did not prevent the observation of relevant sorption features for metal cations, especially for Pb(II) and Cd(II). Rate constants (1-14 g/mg min(-1)) and affinity constants (79-370L/mg) in the same order of magnitude of chitosan-based sorbents were determined, whereas capacities (2-24 mg/g) were smaller than the generality of those same sorbents. Globally, the sorption of metal cations by the Fd composite was superior to that by the CS composite. Furthermore, high stability of the sorbents and acceptable reproducibility of the synthesis was observed. Overall, the developed scheme of immobilization of CS and Fd appears capable of providing an effective way for integrating these biopolymers into metal cation-related applications such as biosorption, sensing or separation.

Abstract This work reports experimental vapour pressures at different temperatures of four halogenated acetophenones. The liquid phase vapour pressures of p-fluoro and p-chloro acetophenones were measured, respectively, across the temperatures ranges (255.1 to 310.2) K and (271.6 to 335.0) K, using a static method based on capacitance diaphragm manometers. This experimental technique was also used to measure the vapour pressures of both (crystalline and liquid) condensed phases of p-bromo-and p-iodoacetophenones, respectively, through the temperature intervals (295.3 to 378.4) K and (313.1 to 402.0) K. The temperatures and molar enthalpies and entropies of fusion of the four p-halogenated acetophenones were determined using differential scanning calorimetry. The standard molar enthalpies, entropies and Gibbs energies of sublimation and of vaporisation, at selected reference temperatures, were derived from the experimental results. The contributions of the acetyl group and of the constituent halogen atoms to these thermodynamic properties were also predicted through correlation equations.

Abstract Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict. © 2016 Peón, Dang and Ballester.

Abstract A sensitive electrochemical sensor was successfully developed based on a glassy carbon (GC) electrode modified by a combination of multi-walled carbon nanotubes (MWCNT) with beta-cyclodextrin (beta-CD) incorporated in a polyaniline film, and applied to detect and determine the fungicide pyrimethanil in pome fruit (apples). The beta-CD/MWCNT modified GC electrode displayed a detection limit of 1.04 mu M (0.21 mg/kg) which is below the maximum residue levels set for pyrimethanil in pome fruit and citrus fruit by EU regulations. The results indicate that the (beta-CD/MWCNT modified GC electrode exhibits efficient electrocatalytic oxidation of pyrimethanil with high reproducibility, repeatability and stability. Furthermore, the obtained results were in excellent agreement with those obtained using an established HPLC procedure.

Abstract Different kinds of molecularly imprinted particles were synthesized and compared, aiming at the development of materials combining high molecular recognition capabilities and facile use as column packing materials for chromatographic aqueous applications. Solution, inverse-suspension and precipitation polymerization were considered and two different model molecules (5-fluorouracil and caffeine) were used to highlight the effect of the interaction between the template molecule and the functional monomer on imprinting efficiency. Particles synthesized through the proposed inverse-suspension process exhibit facile use for packing columns, allow the stable running of chromatographic systems and present a high performance in drug uptake and release in aqueous media. Frontal analysis measurements highlight these key features of the synthesized particles. Drug sorption capabilities of 0.890 mu mol/g and 5.774 mu mol/g were measured for 5-fluorouracil and caffeine, respectively, using frontal analysis with eluents containing the target molecules at concentration 0.1 mM. Due to the lower amount of solvent required than with precipitation polymerization, the developed inverse-suspension process presents high synthesis yields, which can be exploited for the large-scale manufacture and commercialization of molecularly imprinted materials. The combined features of the particles makes possible their direct use in bioseparations or in the development of assays and pharmacokinetic studies concerning the presence of drugs in biological fluids.

Abstract Novel results concerning the inverse vulcanization of sulfur using reversible addition-fragmentation chain transfer (RAFT) polymerization are here reported. It is shown that RAFT polymerization can be used to carry out this crosslinking process, with the additional possibility to extend the reaction time from a few minutes as with classical free radical polymerization (FRP) to several hours. Higher control on viscosity and processability of the synthesized networks, as well as, the implementation of semibatch feed policies during crosslinking are important advantages of the RAFT process here explored comparatively to the FRP inverse vulcanization. Using cyclic voltammetry, it was assessed the electrochemical activity of the synthesized sulfur-rich polymer networks. It is shown that the fundamental electrochemical activity of the elemental sulfur was preserved in the produced materials. Testing of electrochemical cells assembled with lithium in the anode and different sulfur based materials in the cathode, including the synthesized RAFT networks, is also shown. The results here presented highlight the new opportunities introduced by reversible-deactivation radical polymerization mechanisms on the control of the synthesis process and in the design of such advanced materials and show also that many potential derivatizing possibilities can be achieved. (c) 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43993.

Abstract Carbon nanomaterials are the focus of an intense research in several areas of science. Due to their apparent low toxicity, when compared to other nanomaterials, carbon based nanoparticles found particularly important applications in biomedicine. Indeed, carbon shows many nanoallotropic forms like carbon nanotubes, graphene, carbon dots, fullerene and nanodiamonds. Some of them show fluorescence in the visible wavelength range, like graphene and carbon dots, but all have in common being nanosized with the corresponding properties. The main theranostics applications of carbon based nanomaterials (the fluorescent nanoallotropes) are for improving tumor imaging, allowing earlier detection, and specific drug delivery allowing high treatment efficient and reduced side effects. This chapter will describe the carbon nanomaterials mostly used for tumor targeting theranostics, their properties and the engineering strategies used to modify them. Also, the most successful biomedical applications of the carbon nanomaterials will be described. © 2016 by Higher Education Press Limited Company and World Scientific Publishing Co. Pte. Ltd. All rights reserved.

Abstract In the present study, aqueous solutions of a thermo-responsive negatively charged triblock copolymer methoxy-poly(ethylene glycol)-block-poly(N-isopropylacrylamide)-block-poly (2-succinic acid-propyloxyl methacrylate) (MPEG(45)-b-PNIPAAM(48)-b-PSAPMA(10)), have been characterized in the presence of sodium dodecyl sulfate (SDS) or dodecyltrimethylammonium bromide (DTAB) surfactant, at a constant concentration of polymer and various levels of surfactant addition. For this purpose, dynamic light scattering (DLS) was used to probe the effect of the ionic surfactants on the size of the block copolymer species, and small angle neutron scattering (SANS) was applied as a complementary technique to probe the structure on a mesoscopic length scale. The results obtained revealed that the addition of a surfactant to the copolymer solution leads to a decrease of the particle size, due to electrostatic repulsions and solubilization of the hydrophobic microdomains. By zeta potential analysis it was shown that the charge density of the surfactant-coated polymer moieties increases with increasing surfactant concentration. The turbidities of the polymer-surfactant mixtures were measured using a cloud point analyzer. Our data revealed that the behavior not only depends on the surfactant concentration, but it is also affected in some cases by temperature. In addition, cytotoxicity studies were carried out on mouse fibroblasts cells NIH-3T3 to evaluate the potential of the systems as drug delivery carriers. Results showed that the cytotoxicity of the polymer changes with surfactant addition, rising as the concentration of SDS increases but falling off with increasing DTAB concentration.

Abstract Glioblastoma (GBM), the highest grade astrocytoma, is one of the most aggressive and challenging cancers to treat. The standard treatment is usually limited due to the intrinsic resistance of GBM to chemotherapy and drug non-specific effects. Therefore, new therapeutic strategies need to be developed to target tumor cells, sparing healthy tissues. In this context, the inhibitor-of-apoptosis protein (IAP) survivin emerges as an ideal target for a gene silencing approach, since it is sharply differentially expressed in cancer tissues. In this work, two different families of cationic gemini surfactants (bis-quat conventional and serine-derived) were tested regarding their efficiency to deliver small interfering RNAs (siRNAs) in a human GBM cell line (U87), in order to select an effective siRNA anti-survivin carrier. Importantly, survivin downregulation combined with administration of the chemotherapeutic agents temozolomide or etoposide resulted in a synergistic cytotoxic effect, thus revealing to be a promising strategy to reduce the chemotherapeutic doses for GBM treatment.