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- Combination of chemotherapy and Au-nanoparticle photothermy in the visible light to tackle doxorubicin resistance in cancer cellsPublication . Pedrosa, Pedro; Mendes, Rita; Cabral, Rita; Martins, Luisa; Baptista, Pedro; Fernandes, AlexandraDespite great advances in the fight against cancer, traditional chemotherapy has been hindered by the dose dependent adverse side effects that reduce the usable doses for effective therapy. This has been associated to drug resistance in tumor cells that often cause relapse and therapy failure. These drawbacks have been tackled by combining different therapeutic regiments that prevent drug resistance while decreasing the chemotherapy dose required for efficacious ablation of cancer. In fact, new metallic compounds have been in a continuous development to extend the existing chemotherapy arsenal for these combined regimens. Here, we demonstrate that combination of a metallic compound (TS265), previously characterized by our group, with photothermy circumvents cells resistant to Doxorubicin (DOX). We first engendered a colorectal carcinoma cell line (HCT116) highly resistant to DOX, whose viability was diminished after administration of TS265. Cancer cell death was potentiated by challenging these cells with 14 nm spherical gold nanoparticles followed by laser irradiation at 532 nm. The combination of TS265 with photothermy lead to 65% cell death of the DOX resistant cells without impacting healthy cells. These results support the use of combined chemotherapy and photothermy in the visible spectrum as an efficient tool for drug resistant tumors.
- Multifunctional gold-nanoparticles: A nanovectorization tool for the targeted delivery of novel chemotherapeutic agentesPublication . Fernandes, Alexandra; Jesus, João; Martins, Pedro; Figueiredo, Sara; Rosa, Daniela; Martins, Luisa; Corvo, M. Luísa; Carvalheiro, Manuela; Costa, Pedro M.; Baptista, PedroDue to their small size and unique properties, multifunctional nanoparticles arise as versatile delivery systems easily grafted with a vast array of functional moieties, such as anticancer cytotoxic chemotherapeutics and targeting agents. Here, we formulated a multifunctional gold-nanoparticle (AuNP) system composed of a monoclonal antibody against epidermal growth factor receptor (EGFR) (anti-EGFR D-11) for active targeting and a Co(II) coordination compound [CoCl(H2O)(phendione)2][BF4] (phendione = 1,10-phenanthroline-5,6-dione) (TS265) with proven antiproliferative activity towards cancer cells (designated as TargetNanoTS265). The efficacy of this nanoformulation, and the non-targeted counterpart (NanoTS265), were evaluated in vitro using cancer cell models and in vivo using mice xenografts. Compared to the free compound, both nanoformulations (TargetNanoTS265 and NanoTS265) efficiently delivered the cytotoxic cargo in a controlled selective manner due to the active targeting, boosting tumor cytotoxicity. Treatment of HCT116-derived xenografts tumors with TargetNanoTS265 led to 93% tumor reduction. This simple conceptual nanoformulation demonstrates the potential of nanovectorization of chemotherapeutics via simple assembly onto AuNPs of BSA/HAS-drug conjugates that may easily be expanded to suit other cargo of novel compounds that require optimized controlled delivery to cancer target.
- Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivoPublication . Lenis-Rojas, Oscar A.; Robalo, Maria Paula; Tomaz, Ana Isabel; Carvalho, Andreia; Fernandes, Alexandra; Marques, Fernanda; FOLGUEIRA, MONICA; Yáñez, Julián; Vázquez-García, Digna; López-Torres, Margarita; Fernandez, Alberto; Fernandez, Jesus J.Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru(p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru(p-cymene)(Cl)(μ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV–vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru(p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.
- Half-sandwich Ru(p-cymene) compounds with diphosphanes: In Vitro and In Vivo evaluation as potential anticancer metallodrugsPublication . Lenis Rojas, Oscar; Robalo, M. Paula; Tomaz, Ana Isabel; Fernandes, Alexandra; Roma-Rodrigues, Catarina; Gonçalves Teixeira, Ricardo; Marques, Fernanda; FOLGUEIRA, MONICA; Yáñez, Julián; Alba-González, Anabel; Salamini-Montemurri, Martin; Pech-Puch, Dawrin; Vázquez-García, Digna; López-Torres, Margarita; Fernandez, Alberto; Fernandez, Jesus J.Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl]-[CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, H-1 and P-31{H-1} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.
- Evaluation of cell toxicity and DNA and protein binding of green synthesized silver nanoparticlesPublication . Da Costa Ribeiro, Ana Paula; Anbu, S; Alegria, Elisabete; Fernandes, Alexandra; Baptista, Pedro; Mendes, Rita; Matias, A. S.; Mendes, M.; Guedes Da Silva, M. Fátima C.; Pombeiro, ArmandoSilver nanoparticles (AgNPs) were prepared by GREEN chemistry relying on the reduction of AgNO3 by phytochemicals present in black tea extract. AgNPs were fully characterized by transmission electron microscopy (TEM), ultraviolet-visible spectroscopy ((UV-vis)), X-ray diffraction (XRD) and energy dispersive absorption spectroscopy (EDS). The synthesized AgNPs induced a decrease of the cell viability in a dose-dependent manner with a low IC50 (0.5 +/- 0.1 mu M) for an ovarian carcinoma cell line (A2780) compared to primary human fibroblasts (IC50 5.0 +/- 0.1 mu M). The DNA binding capability of CT (calf thymus) DNA was investigated using electronic absorption and fluorescence spectroscopies, circular dichroism and viscosity titration methods. Additionally, the AgNPs strongly quench the intrinsic fluorescence of BSA, as determined by synchronous fluorescence spectra.
- First heterobimetallic Cu(i)-dppf complexes designed for anticancer applications: synthesis, structural characterization and cytotoxicityPublication . Bravo, Catarina; M. Paula Robalo; Marques, Fernanda; Fernandes, Alexandra; Sequeira, Diogo A.; M. Fatima M. Piedade; Garcia, M. Helena; Villa De Brito, Maria José; Morais, TâniaA new family of eight heterobimetallic Cu(i)-dppf complexes of general formula [Cu(dppf)L][BF4] with dppf = 1,1 '-bis(diphenylphosphino)ferrocene and L representing N,N-, N,O- and N,S-heteroaromatic bidentate ligands have been synthesized and fully characterized by classical analytical, spectroscopic and electrochemical methods. The single crystal structures of [Cu(dppf)(pBI)][BF4] (6), [Cu(dppf)(dpytz)][BF4] (7) and [Cu(dppf)(5-Aphen)][BF4] (8) complexes (where pBI = 2-(2-pyridyl)benzimidazole, dpytz = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine and 5-Aphen = 1,10-phenanthrolin-5-amine) were determined by X-ray diffraction studies. Cytotoxicity of all complexes was evaluated in two human breast adenocarcinoma cell lines (MCF7 and MDAMB231). All the complexes exhibit high cytotoxicity against both human breast cancer cells with IC50 values far lower than those found for the antitumor drug cisplatin in the same cell lines. The IC50 values on primary healthy fibroblasts are of the same order of magnitude as those found for the tumoral cells.
- Antiproliferative activity of heterometallic sodium and potassium-dioxidovanadium(V) polymersPublication . Sutradhar, Manas; Alegria, Elisabete; Ferretti, Francesco; Raposo, Luís R; Guedes Da Silva, M. Fátima C.; Baptista, Pedro; Fernandes, Alexandra; Pombeiro, ArmandoThe syntheses of the heterometallic sodium and potassium-dioxidovanadium 2D polymers, [NaVO2(1 kappa NOO';2 kappa O ''-L)(H2O)](n), (1) and [KVO2(1 kappa NOO';2 kappa O';3 kappa O ''-L)(EtOH)](n) (2) (where the kappa notation indicates the coordinating atoms of the polydentate ligand L) derived from (3,5-di-tert-butyl-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H2L) are reported. The polymers were characterized by IR, NMR, elemental analysis and single crystal X-ray diffraction analysis. The antiproliferative potential of 1 and 2 was examined towards four human cancer cell lines (ovarian carcinoma, A2780, colorectal carcinoma, HCT116, prostate carcinoma, PC3 and breast adenocarcinoma, MCF-7cell lines) and normal human fibroblasts. Complex 1 and 2 showed the highest cytotoxic activity against A2780 cell line (IC50 8.2 and 11.3 mu M, respectively) with 1 > 2 and an IC50 in the same range as cisplatin (IC50 3.4 mu M; obtained in the same experimental conditions) but, interestingly, with no cytotoxicity to healthy human fibroblasts for concentrations up to 75 mu M. This high cytotoxicity of 1 in ovarian cancer cells and its low cytotoxicity in healthy cells demonstrates its potential for further biological studies. Our results suggest that both complexes induce ovarian carcinoma cell death via apoptosis and autophagy, but autophagy is the main biological cause of the reduction of viability observed and that ROS (reactive oxygen species) may play an important role in triggering cell death.