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Centre for Nuclear Sciences and Technologies
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Enhancing the magnetic properties of superparamagnetic iron oxide nanoparticles using hydrothermal treatment for magnetic hyperthermia application
Publication . Martins, Carla; Rolo, Catarina; Cacho, Vanessa R. G.; Pereira, Laura C. J.; Borges, João Paulo; Silva, Jorge Carvalho; Vieira, Tânia; Soares, Paula I. P.; CENIMAT-i3N - Centro de Investigação de Materiais (Lab. Associado I3N); DCM - Departamento de Ciência dos Materiais; DF – Departamento de Física; RSC - Royal Society of Chemistry
Superparamagnetic iron oxide nanoparticles (SPIONs) are the most commonly used inorganic nanoparticles for magnetic hyperthermia in cancer treatment. In this technique, the temperature of the tumor is increased by applying an external alternating magnetic field, which induces heat release from magnetic nanoparticles located at the tumor site. In this study, SPIONs were produced using the chemical co-precipitation technique combined with hydrothermal treatment to reduce their size dispersibility and increase their crystallinity, which are directly related to their magnetic properties. The size of the SPIONs increased from 9 nm to 20 nm after hydrothermal treatment at 160 °C for 24 h. These NPs exhibit a cubic/rectangular shape with a structure composed of both magnetite and maghemite. Their superparamagnetic behavior was confirmed, and the magnetic saturation increased from 58 to 73 emu g−1 at RT and from 67 to 81 emu g−1 at 10 K. Magnetic hyperthermia measurements showed an increase in SAR values from 83 to about 160-200 W g−1, depending on the hydrothermal treatment conditions. Additionally, the exposure of normal and melanoma cells to SPIONs in the presence of an alternating magnetic field leads to a significant reduction in cell viability, with a more pronounced effect in melanoma cells. These results demonstrate the high potential of this synthesis technique for producing SPIONs for cancer treatment via magnetic hyperthermia.
Boron clusters (ferrabisdicarbollides) shaping the future as radiosensitizers for multimodal (chemo/radio/PBFR) therapy of glioblastoma
Publication . Nuez-Martínez, Miquel; Queralt-Martín, María; Muñoz-Juan, Amanda; Aguilella, Vicente M.; Laromaine, Anna; Teixidor, Francesc; Viñas, Clara; Pinto, Catarina G.; Pinheiro, Teresa; Guerreiro, Joana F.; Mendes, Filipa; Roma-Rodrigues, Catarina; Baptista, Pedro V.; Fernandes, Alexandra R.; Valic, Srecko; Marques, Fernanda; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; RSC - Royal Society of Chemistry
Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, and is highly resistant to conventional radiotherapy and chemotherapy. Therefore, the development of multidrug resistance and tumor recurrence are frequent. Given the poor survival with the current treatments, new therapeutic strategies are urgently needed. Radiotherapy (RT) is a common cancer treatment modality for GBM. However, there is still a need to improve RT efficiency, while reducing the severe side effects. Radiosensitizers can enhance the killing effect on tumor cells with less side effects on healthy tissues. Herein, we present our pioneering study on the highly stable and amphiphilic metallacarboranes, ferrabis(dicarbollides) ([o-FESAN]− and [8,8′-I2-o-FESAN]−), as potential radiosensitizers for GBM radiotherapy. We propose radiation methodologies that utilize secondary radiation emissions from iodine and iron, using ferrabis(dicarbollides) as iodine/iron donors, aiming to achieve a greater therapeutic effect than that of a conventional radiotherapy. As a proof-of-concept, we show that using 2D and 3D models of U87 cells, the cellular viability and survival were reduced using this treatment approach. We also tested for the first time the proton boron fusion reaction (PBFR) with ferrabis(dicarbollides), taking advantage of their high boron (11B) content. The results from the cellular damage response obtained suggest that proton boron fusion radiation therapy, when combined with boron-rich compounds, is a promising modality to fight against resistant tumors. Although these results are encouraging, more developments are needed to further explore ferrabis(dicarbollides) as radiosensitizers towards a positive impact on the therapeutic strategies for GBM.
The Conformation of the N-Terminal Tails of Deinococcus grandis Dps Is Modulated by the Ionic Strength
Publication . Guerra, João P. L.; Blanchet, Clement E.; Vieira, Bruno J. C.; Almeida, Ana V.; Waerenborgh, João C.; Jones, Nykola C.; Hoffmann, Søren V.; Tavares, Pedro; Pereira, Alice S.; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; MDPI - Multidisciplinary Digital Publishing Institute
DNA-binding proteins from starved cells (Dps) are homododecameric nanocages, with N-and C-terminal tail extensions of variable length and amino acid composition. They accumulate iron in the form of a ferrihydrite mineral core and are capable of binding to and compacting DNA, forming low-and high-order condensates. This dual activity is designed to protect DNA from oxidative stress, resulting from Fenton chemistry or radiation exposure. In most Dps proteins, the DNA-binding properties stem from the N-terminal tail extensions. We explored the structural characteristics of a Dps from Deinococcus grandis that exhibits an atypically long N-terminal tail composed of 52 residues and probed the impact of the ionic strength on protein conformation using size exclusion chromatography, dynamic light scattering, synchrotron radiation circular dichroism and small-angle X-ray scattering. A novel high-spin ferrous iron-binding site was identified in the N-terminal tails, using Mössbauer spectroscopy. Our data reveals that the N-terminal tails are structurally dynamic and alter between compact and extended conformations, depending on the ionic strength of the buffer. This prompts the search for other physiologically relevant modulators of tail conformation and hints that the DNA-binding properties of Dps proteins may be affected by external factors.
Controlled modulation of the dynamics of the Deinococcus grandis Dps N-terminal tails by divalent metals
Publication . Guerra, João P. L.; Blanchet, Clement E.; Vieira, Bruno J. C.; Waerenborgh, João C.; Jones, Nykola C.; Hoffmann, Søren Vrønning; Pereira, Alice S.; Tavares, Pedro; DQ - Departamento de Química; UCIBIO - Applied Molecular Biosciences Unit; Wiley-Blackwell
DNA-binding proteins from starved cells (Dps) are small multifunctional nanocages expressed by prokaryotes in acute oxidative stress conditions or during the starvation-induced stationary phase, as a bacterial defense mechanism. Dps proteins protect bacterial DNA from damage by either direct binding or by removing precursors of reactive oxygen species from solution. The DNA-binding properties of most Dps proteins studied so far are related to their unordered, flexible, N- and C-terminal extensions. In a previous work, we revealed that the N-terminal tails of Deinoccocus grandis Dps shift from an extended to a compact conformation depending on the ionic strength of the buffer and detected a novel high-spin ferrous iron center in the proximal ends of those tails. In this work, we further explore the conformational dynamics of the protein by probing the effect of divalent metals binding to the tail by comparing the metal-binding properties of the wild-type protein with a binding site-impaired D34A variant using size exclusion chromatography, dynamic light scattering, synchrotron radiation circular dichroism, and small-angle X-ray scattering. The N-terminal ferrous species was also characterized by Mössbauer spectroscopy. The results herein presented reveal that the conformation of the N-terminal tails is altered upon metal binding in a gradual, reversible, and specific manner. These observations may point towards the existence of a regulatory process for the DNA-binding properties of Dps proteins through metal binding to their N- and/or C-terminal extensions.
Tuning the Biological Activity of Camphorimine Complexes through Metal Selection
Publication . Costa, Joana P.; Pinheiro, Teresa; Martins, Maria S.; Carvalho, M. Fernanda N. N.; Feliciano, Joana; Leitão, Jorge H.; Silva, R. A. L.; Guerreiro, Joana F; Alves, Luís C.; Custódio, Inês; Cruz, J.; Marques, Fernanda; DF – Departamento de Física; MDPI - Multidisciplinary Digital Publishing Institute
The cytotoxic activity of four sets of camphorimine complexes based on the Cu(I), Cu(II), Ag(I), and Au(I) metal sites were assessed against the cisplatin-sensitive A2780 and OVCAR3 ovarian cancer cells. The results showed that the gold complexes were ca. one order of magnitude more active than the silver complexes, which in turn were ca. one order of magnitude more active than the copper complexes. An important finding was that the cytotoxic activity of the Ag(I) and Au(I) camphorimine complexes was higher than that of cisplatin. Another relevant aspect was that the camphorimine complexes did not interact significantly with DNA, in contrast with cisplatin. The cytotoxic activity of the camphorimine complexes displayed a direct relationship with the cellular uptake by OVCAR3 cells, as ascertained by PIXE (particle-induced X-ray emission). The levels of ROS (reactive oxygen species) formation exhibited an inverse relationship with the reduction potentials for the complexes with the same metal, as assessed by cyclic voltammetry. In order to gain insight into the toxicity of the complexes, their cytotoxicity toward nontumoral cells (HDF and V79 fibroblasts) was evaluated. The in vivo cytotoxicity of complex 5 using the nematode Caenorhabditis elegans was also assessed. The silver camphorimine complexes displayed the highest selectivity coefficients (activity vs. toxicity).
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
6817 - DCRRNI ID
Número da atribuição
UID/Multi/04349/2019