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2015
Palma, SI, Carvalho A, Silva J, Martins P, Marciello M, Fernandes AR, Del Puerto Morales M, Roque AC.  2015.  Covalent coupling of gum arabic onto superparamagnetic iron oxide nanoparticles for MRI cell labeling: physicochemical and in vitro characterization. Contrast Media Mol Imaging. 10:320-8., Number 4 AbstractWebsite

Gum arabic (GA) is a hydrophilic composite polysaccharide derived from exudates of Acacia senegal and Acacia seyal trees. It is biocompatible, possesses emulsifying and stabilizing properties and has been explored as coating agent of nanomaterials for biomedical applications, namely magnetic nanoparticles (MNPs). Previous studies focused on the adsorption of GA onto MNPs produced by co-precipitation methods. In this work, MNPs produced by a thermal decomposition method, known to produce uniform particles with better crystalline properties, were used for the covalent coupling of GA through its free amine groups, which increases the stability of the coating layer. The MNPs were produced by thermal decomposition of Fe(acac)3 in organic solvent and, after ligand-exchange with meso-2,3-dimercaptosuccinic acid (DMSA), GA coating was achieved by the establishment of a covalent bond between DMSA and GA moieties. Clusters of several magnetic cores entrapped in a shell of GA were obtained, with good colloidal stability and promising magnetic relaxation properties (r2 /r1 ratio of 350). HCT116 colorectal carcinoma cell line was used for in vitro cytotoxicity evaluation and cell-labeling efficiency studies. We show that, upon administration at the respective IC50 , GA coating enhances MNP cellular uptake by 19 times compared to particles bearing only DMSA moieties. Accordingly, in vitro MR images of cells incubated with increasing concentrations of GA-coated MNP present dose-dependent contrast enhancement. The obtained results suggest that the GA magnetic nanosystem could be used as a MRI contrast agent for cell-labeling applications.

I.C.J.Palma, S, Carvalho A, Silva J, Fernandes AR, del Puerto-Morales M, Roque ACA.  2015.  Covalent coupling of gum arabic onto superparamagnetic iron oxide nanoparticles for MRI cell labeling: physiochemical and in vitro characterization. Contrast Media and Molecular Imaging. AbstractWebsite

Gum arabic (GA) is a hydrophilic composite polysaccharide derived from exudates of Acacia senegal and Acacia seyal trees. It is biocompatible, possesses emulsifying and stabilizing properties and has been explored as coating agent of nanomaterials for biomedical applications, namely magnetic nanoparticles (MNPs). Previous studies focused on the adsorption of GA onto MNPs produced by co-precipitation methods. In this work, MNPs produced by a thermal decomposition method, known to produce uniform particles with better crystalline properties, were used for the covalent coupling of GA through its free amine groups, which increases the stability of the coating layer. The MNPs were produced by thermal decomposition of Fe(acac)3 in organic solvent and, after ligand-exchange with meso-2,3-dimercaptosuccinic acid (DMSA), GA coating was achieved by the establishment of a covalent bond between DMSA and GA moieties. Clusters of several magnetic cores entrapped in a shell of GA were obtained, with good colloidal stability and promising magnetic relaxation properties (r2 /r1 ratio of 350). HCT116 colorectal carcinoma cell line was used for in vitro cytotoxicity evaluation and cell-labeling efficiency studies. We show that, upon administration at the respective IC50 , GA coating enhances MNP cellular uptake by 19 times compared to particles bearing only DMSA moieties. Accordingly, in vitro MR images of cells incubated with increasing concentrations of GA-coated MNP present dose-dependent contrast enhancement. The obtained results suggest that the GA magnetic nanosystem could be used as a MRI contrast agent for cell-labeling applications.

Aroso, IM, Craveiro R, Rocha A, Dionísio M, Barreiros S, Reis RL, Paiva A, Duarte ARC.  2015.  Design of controlled release systems for THEDES—Therapeutic deep eutectic solvents, using supercritical fluid technology. International Journal of Pharmaceutics. 492:73-79.Website
Palma, SI, Marciello M, Carvalho A, Veintemillas-Verdaguer S, Morales PM, Roque ACA.  2015.  Effects of phase transfer ligands on monodisperse iron oxide magnetic nanoparticles. Journal of Colloid & Interface Science. 437(1):147–155. AbstractWebsite

Oleic acid coated iron oxide nanoparticles synthesized by thermal decomposition in organic medium are highly monodisperse but at the same time are unsuitable for biological applications. Ligand-exchange reactions are useful to make their surface hydrophilic. However, these could alter some structural and magnetic properties of the modified particles. Here we present a comprehensive study and comparison of the effects of employing either citric acid (CA) or meso-2,3-dimercaptosuccinic acid (DMSA) ligand-exchange protocols for phase transfer of monodisperse hydrophobic iron oxide nanoparticles produced by thermal decomposition of Fe(acac)3 in benzyl ether. We show the excellent hydrodynamic size distribution and colloidal stability of the hydrophilic particles obtained by the two protocols and confirm that there is a certain degree of oxidation caused by the ligand-exchange. CA revealed to be more aggressive towards the iron oxide surface than DMSA and greatly reduced the saturation magnetization values and initial susceptibility of the resulting particles compared to the native ones. Besides being milder and more straightforward to perform, the DMSA ligand exchange protocol produces MNP chemically more versatile for further functionalization possibilities. This versatility is shown through the covalent linkage of gum Arabic onto MNP-DMSA using carboxyl and thiol based chemical routes and yielding particles with comparable properties.

Martins, P, Jesus J, Santos S, Raposo LR, Roma-Rodrigues C, Baptista PV, Fernandes AR.  2015.  Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box. Molecules. 9(20):16852-16891. AbstractWebsite

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.

Loureiro, J, Mateus T, Filonovich S, Ferreira M, Figueira J, Rodrigues A, Donovan BF, Hopkins PE, Ferreira I.  2015.  Hydrogenated nanocrystalline silicon thin films with promising thermoelectric properties. Appl. Phys. A. 120(4):1497–1502. AbstractWebsite

The search for materials with suitable thermoelectric properties that are environmentally friendly and abundant led us to investigate p- and n-type hydrogenated nanocrystalline silicon (nc-Si:H) thin films, produced by plasma-enhanced chemical vapor deposition. The Seebeck coefficient and power factor were measured at room temperature showing optimized values of 512 µV K−1 and 3.6 × 10−5 W m−1 K−2, for p-type, and −188 µV K−1 and 2.2 × 10−4 W m−1 K−2, for n-type thin films. The thermoelectric output power of one nc-Si:H pair of both n- and p-type materials is ~91 µW per material cm3, for a thermal gradient of 8 K. The output voltage and current values show a linear dependence with the number of pairs interconnected in series and/or parallel and show good integration performance.

Roma-Rodrigues, C, Barroco C, Raposo LR, Costa MN, Fortunato E, Baptista PV, Fernandes AR, Santos-Sanches I.  2015.  Infection of human keratinocytes by Streptococcus dysgalactiae subspecies dysgalactiae isolated from milk of the bovine udder.. Microbes and Infection. 4(18):290-3. AbstractWebsite

Streptococcus dysgalactiae subsp. dysgalactiae (SDSD) are considered exclusive animal pathogens; however, a putative zoonotic upper limb cellulitis, a prosthetic joint infection and an infective endocarditis were described in humans. To unravel if bovine SDSD isolates are able to infect human cells, the adherence and internalization to human primary keratinocytes of two bovine SDSD strains isolated from milk collected from udder were analyzed. Bacterial adhesion assays and confocal microscopy indicate a high adherence and internalization of SDSD isolates to human cells, suggesting for the first time the ability of bovine isolates to infect human cells.

Fortes, P, Alvarenga A, Seixas J, Rodrigues S.  2015.  Long term energy scenarios: Bridging the gap between socio-economic storylines and energy Modeling. Technological Forecasting & Social Change. 91:161-178.Website
Roma-Rodrigues, C, Raposo LR, Fernandes AR.  2015.  microRNAs based therapy of Hypertrophic cardiomyopathy: the road traveled so far. BioMed Research International. :983290. AbstractWebsite

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by variable expressivity, age penetrance, and a high heterogeneity. The transcriptional profile (miRNAs, mRNAs), epigenetic modifications, and posttranslational modifications seem to be highly relevant for the onset of the disease. miRNAs, small noncoding RNAs with 22 nucleotides, have been implicated in the regulation of cardiomyocyte function, being differentially expressed in several heart diseases, including HCM. Moreover, a different miRNA expression profile in the various stages of HCM development is also observed. This review summarizes the current knowledge of the profile of miRNAs characteristic of asymptomatic to overt HCM patients, discussing alongside their potential use for diagnosis and therapy. Indeed, the stability and specificity of miRNAs make them suitable targets for use as biomarkers for diagnosis and prognosis and as therapeutical targets.

Pina, AS, Dias AMGC, Ustok FI, Khoury GE, Fernandes CSM, Branco RJF, Lowe CR, Roque ACA.  2015.  Mild and cost-effective green fluorescent protein purification employing small synthetic ligands. Journal of Chromatography A. 1418:83-93. AbstractWebsite

Abstract The green fluorescent protein (GFP) is a useful indicator in a broad range of applications including cell biology, gene expression and biosensing. However, its full potential is hampered by the lack of a selective, mild and low-cost purification scheme. In order to address this demand, a novel adsorbent was developed as a generic platform for the purification of \{GFP\} or \{GFP\} fusion proteins, giving \{GFP\} a dual function as reporter and purification tag. After screening a solid-phase combinatorial library of small synthetic ligands based on the Ugi-reaction, the lead ligand (A4C7) selectively recovered \{GFP\} with 94% yield and 94% purity under mild conditions and directly from Escherichia coli extracts. Adsorbents containing the ligand \{A4C7\} maintained the selectivity to recover other proteins fused to GFP. The performance of \{A4C7\} adsorbents was compared with two commercially available methods (immunoprecipitation and hydrophobic interaction chromatography), confirming the new adsorbent as a low-cost viable alternative for \{GFP\} purification.

A. C. Marques, L. Santos, M. N. Costa, J. M. Dantas, P. Duarte, A. Gonçalves, R. Martins, C. A. Salgueiro, Fortunato E.  2015.  Office Paper Platform for Bioelectrochromic Detection of Electrochemically Active Bacteria using Tungsten Trioxide Nanoprobes. Nature Publishing Group Scientific Reports. 5
Echeverria, C, Soares PIP, Robalo A, Pereira L, Novo C, Ferreira I, Borges JP.  2015.  One-pot synthesis of dual-stimuli responsive hybrid PNIPAAm-chitosan microgels. Materials & Design. 86:745-751. AbstractWebsite

The incorporation of magnetic nanoparticles into poly(N-isopropylacrylamide) (PNIPAAm) and chitosan microgels gives rise to hybrid systems that combine the microgels swelling capacity with the interesting features presented in magnetic nanoparticles. The presence of chitosan that act as surfactant for magnetic nanoparticles provides a simplistic approach which allows the encapsulation of magnetic nanoparticles without any previous surface modification. Spherical and highly monodisperse microgels with diameters in the range of 200 to 500 nm were obtained. The encapsulation of magnetic nanoparticles in the polymer matrix was confirmed by high resolution Scanning Electron Microscopy in transmission mode. Volume phase transition of the microgels was accessed by Dynamic Light Scattering measurements. It was observed that the thermosensitivity of the PNIPAM microgels still persists in the hybrid microgels; however, the swelling ability is compromised in the microgels with highest chitosan content. The heating performance of the hybrid magnetic microgels, when submitted to an alternating magnetic field, was also evaluated demonstrating the potential of these systems for hyperthermia treatments.

Echeverria, C, Soares P, Robalo A, Pereira L, Novo CMM, Ferreira I, Borges JP.  2015.  One-pot synthesis of dual-stimuli responsive hybrid PNIPAAm-chitosan microgels. Mater. Des. 86:745-751. AbstractWebsite

The incorporation of magnetic nanoparticles into poly(N-isopropylacrylamide) (PNIPAAm) and chitosan microgels gives rise to hybrid systems that combine the microgels swelling capacity with the interesting features presented in magnetic nanoparticles. The presence of chitosan that act as surfactant for magnetic nanoparticles provides a simplistic approach which allows the encapsulation of magnetic nanoparticles without any previous surface modification. Spherical and highly monodisperse microgels with diameters in the range of 200 to 500 nm were obtained. The encapsulation of magnetic nanoparticles in the polymer matrix was confirmed by high resolution Scanning Electron Microscopy in transmission mode. Volume phase transition of the microgels was accessed by Dynamic Light Scattering measurements. It was observed that the thermosensitivity of the PNIPAM microgels still persists in the hybrid microgels; however, the swelling ability is compromised in the microgels with highest chitosan content. The heating performance of the hybrid magnetic microgels, when submitted to an alternating magnetic field, was also evaluated demonstrating the potential of these systems for hyperthermia treatments.

Rodrigues, L. C., Mata, D., Pimentel, Nunes, D., Martins, Fortunato, Neves, Nuno, Monteiro, T., Costa FM.  2015.  One-step synthesis of ZnO decorated CNT buckypaper composites and their optical and electrical properties. Materials Science and Engineering: B. 195:38-44.
Cerqueira, N, Gonzalez PJ, Fernandes PA, Moura JJG, Ramos MJ.  2015.  Periplasmic nitrate reductase and formate dehydrogenase: similar molecular architectures with very different enzymatic activities. Acc Chem Res. 48:2875−2884.
Restani, RB, Conde J, Pires RF, Martins P, Fernandes AR, Baptista PV, Bonifácio VDB, Aguiar-Ricardo A.  2015.  POxylated polyurea dendrimers: Smart core-shell vectors with IC50 lowering capacity. Macromol. Biosci.. AbstractWebsite

The design and preparation of highly efficient drug delivery platforms using green methodologies is at the forefront of nanotherapeutics research. POxylated polyurea dendrimers are efficiently synthesized using a supercritical-assisted polymerization in carbon dioxide. These fluorescent, pH-responsive and water-soluble core-shell smart nanocarriers show low toxicity in terms of cell viability and absence of glutathione depletion, two of the major side effect limitations of current vectors. The materials are also found to act as good transfection agents, through a mechanism involving an endosomal pathway, being able to reduce 100-fold the IC50 of paclitaxel.

Mano, F, Aroso I, Barreiros S, Borges JP, Reis R, Duarte AR, Paiva A.  2015.  Production of Poly(vinyl alcohol) (PVA) Fibers with Encapsulated Natural Deep Eutectic Solvent (NADES) Using Electrospinning. ACS Sustainable Chemistry & Engineering. 3(10):2504–2509. AbstractWebsite

Functionalized electrospun fibers are of great interest for biomedical applications such as in the design of drug delivery systems. Nevertheless, in some cases the molecules of interest have poor solubility in water or have high melting temperatures. These drawbacks can be overcome using deep eutectic solvents. In this work, poly(vinyl alcohol) (PVA), a common biodegradable biopolymer, was used to produce new functionalized fibers with the eutectic mixture choline chloride:citric acid in a molar ratio of (1:1) ChCl:CA (1:1), which was used as a model system. Fibers were produced from an aqueous solution with 7.8% (w/v) and 9.8% (w/v) of 95% hydrolyzed PVA and a 2% (v/v) of ChCl:CA (1:1). Smooth, uniform fibers with an average diameter of 0.4 μm were obtained with a content of 19.8 wt % of ChCl:CA (1:1) encapsulated.

Ferreira, M, Loureiro J, Nogueira A, Rodrigues A, Martins R, Ferreira I.  2015.  SnO2 thin Film Oxides Produced by rf Sputtering for Transparent Thermoelectric Devices. Mater. Today-Proc. 2(2):647-653. AbstractWebsite

The combination of high transparency and good thermoelectric properties of SnO2 can open new field of applications for the thin film thermoelectric materials. Here we report on SnO2 thin films with transmittance above 90%, resistivity bellow 10-3 Ωm and a Power Factor around 10-4 W/m.K2, for a Seebeck of -255 μV/K, at room temperature. The effect of film thickness and post-deposition annealing on the thermoelectric properties were analysed. The performances of a single layer thermoelectric device are also presented.

Reed, P, Atilano ML, Alves R, Hoiczyk E, Sher X, Reichmann NT, Pereira PM, Roemer T, Filipe SR, Pereira-Leal JB, Ligoxygakis P, Pinho MG.  2015.  Staphylococcus aureus survives with a minimal peptidoglycan synthesis machinery but sacrifices virulence and antibiotic resistance. PLoS Pathogens. 11:e1004891.
Carvalho, LCR, Ribeiro D, Seixas RSGR, Silva AMS, Nave M, Martins AC, Erhardt S, Fernandes E, Cabrita EJ, Marques MMB.  2015.  Synthesis and evaluation of new benzimidazole-based COX inhibitors: a naproxen-like interaction detected by STD-NMR. RSC Advances. 5:49098-49109., Number {61} Abstract

Non-steroidal anti-inflammatory drugs exert their pharmacological activity through inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2). Recent research suggests that a balanced inhibition of both COX-1 and COX-2 is the key to reduce the side-effects exhibited by COX inhibitors. We developed new benzimidazole-based compounds that showed a balanced COX inhibition, supported by molecular docking screening. The human whole blood assays demonstrated that the ester derivatives were potent inhibitors. Competitive saturation transfer difference (STD)-NMR experiments, in the presence of COX-2, using naproxen and diclofenac demonstrated that ester derivatives do not compete with diclofenac for the same binding site, but compete with the allosteric inhibitor naproxen. Combination of NMR spectroscopy with molecular docking has permitted us to detect a new naproxen-like inhibitor, which could be used for future drug development.

Palma, SI, Rodrigues CA, Carvalho A, Morales PM, Freitas F, Fernandes AR, Cabral JS, Roque ACA.  2015.  A value-added exopolysaccharide as a coating agent for MRI nanoprobes. Nanoscale. (7):14272-14283. AbstractWebsite

Fucopol, a fucose-containing exopolysaccharide (EPS) produced by the bacterium Enterobacter A47 DSM 23139 using glycerol as a carbon source, was employed as a new coating material for iron oxide magnetic nanoparticles (MNP). The coated particles were assessed as nanoprobes for cell labeling by Magnetic Resonance Imaging (MRI). The MNP were synthesized by a thermal decomposition method and transferred to aqueous medium by ligand-exchange reaction with meso-2,3-dimercaptosuccinic acid (DMSA). Covalent binding of EPS to DMSA-stabilized nanoparticles (MNP-DMSA) resulted in a hybrid magnetic-biopolymeric nanosystem (MNP-DMSA-EPS) with a hydrodynamic size of 170 nm, negative surface charge at physiological conditions and transverse to longitudinal relaxivities ratio, r2/r1, of 148. In vitro studies with two human cell lines (colorectal carcinoma - HCT116 - and neural stem/progenitor cells - ReNcell VM) showed that EPS promotes internalization of nanoparticles in both cell lines. In vitro MRI cell phantoms also showed superior performance of MNP-DMSA-EPS in ReNcell VM, for which iron dose-dependent MRI signal drop was obtained at relatively low iron concentrations (12 - 20 µg Fe/ml) and short incubation time. Furthermore, ReNcell VM multipotency was not affected by culture in the presence of MNP-DMSA or MNP-DMSA-EPS for 14 days. Our study suggests that Fucopol-coated MNP represent useful cell labeling nanoprobes for MRI.

Palma, SICJ, Rodrigues CAV, Freitas F, Carvalho A, Fernandes AR, del Morales MP, Cabral JMS, Roque ACA.  2015.  A value-added exopolysaccharide as a coating agent for MRI nanoprobes. Nanoscale. (7):14272-83. AbstractWebsite

Fucopol, a fucose-containing exopolysaccharide (EPS) produced by the bacterium Enterobacter A47 DSM 23139 using glycerol as a carbon source, was employed as a new coating material for iron oxide magnetic nanoparticles (MNPs). The coated particles were assessed as nanoprobes for cell labeling by Magnetic Resonance Imaging (MRI). The MNPs were synthesized by a thermal decomposition method and transferred to an aqueous medium by a ligand-exchange reaction with meso-2,3-dimercaptosuccinic acid (DMSA). Covalent binding of EPS to DMSA-stabilized nanoparticles (MNP–DMSA) resulted in a hybrid magnetic–biopolymeric nanosystem (MNP–DMSA–EPS) with a hydrodynamic size of 170 nm, a negative surface charge under physiological conditions and transverse to longitudinal relaxivity ratio, r2/r1, of 148. In vitro studies with two human cell lines (colorectal carcinoma – HCT116 – and neural stem/progenitor cells – ReNcell VM) showed that EPS promotes internalization of nanoparticles in both cell lines. In vitro MRI cell phantoms showed a superior performance of MNP–DMSA–EPS in ReNcell VM, for which the iron dose-dependent MRI signal drop was obtained at relatively low iron concentrations (12–20 μg Fe per ml) and short incubation times. Furthermore, ReNcell VM multipotency was not affected by culture in the presence of MNP–DMSA or MNP–DMSA–EPS for 14 days. Our study suggests that Fucopol-coated MNPs represent useful cell labeling nanoprobes for MRI.

Ferraz, R, Costa-Rodrigues J, Fernandes MH, Santos MM, Marrucho IM, Rebelo LPN, Prudencio C, Noronha JP, Petrovski Z, Branco LC.  2015.  Antitumor Activity of Ionic Liquids Based on Ampicillin. Chemmedchem. 10:1480-1483., Number 9 AbstractWebsite
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Correia, HD, Marangon J, Brondino CD, Moura JJG, Romao MJ, Gonzalez PJ, Santos-Silva T.  2015.  Aromatic aldehydes at the active site of aldehyde oxidoreductase from Desulfovibrio gigas: reactivity and molecular details of the enzyme-substrate and enzyme-product interaction. Journal of Biological Inorganic Chemistry. 20:219-229., Number 2 AbstractWebsite

Desulfovibrio gigas aldehyde oxidoreductase (DgAOR) is a mononuclear molybdenum-containing enzyme from the xanthine oxidase (XO) family, a group of enzymes capable of catalyzing the oxidative hydroxylation of aldehydes and heterocyclic compounds. The kinetic studies reported in this work showed that DgAOR catalyzes the oxidative hydroxylation of aromatic aldehydes, but not heterocyclic compounds. NMR spectroscopy studies using C-13-labeled benzaldehyde confirmed that DgAOR catalyzes the conversion of aldehydes to the respective carboxylic acids. Steady-state kinetics in solution showed that high concentrations of the aromatic aldehydes produce substrate inhibition and in the case of 3-phenyl propionaldehyde a suicide substrate behavior. Hydroxyl-substituted aromatic aldehydes present none of these behaviors but the kinetic parameters are largely affected by the position of the OH group. High-resolution crystallographic structures obtained from single crystals of active-DgAOR soaked with benzaldehyde showed that the side chains of Phe(425) and Tyr(535) are important for the stabilization of the substrate in the active site. On the other hand, the X-ray data of DgAOR soaked with trans-cinnamaldehyde showed a cinnamic acid molecule in the substrate channel. The X-ray data of DgAOR soaked with 3-phenyl propionaldehyde showed clearly how high substrate concentrations inactivate the enzyme by binding covalently at the surface of the enzyme and blocking the substrate channel. The different reactivity of DgAOR versus aldehyde oxidase and XO towards aromatic aldehydes and N-heterocyclic compounds is explained on the basis of the present kinetic and structural data.

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