Rute Vitor - Academia.edu (original) (raw)

Papers by Rute Vitor

Artificial cells, nanomedicine, and biotechnology, Jan 12, 2018

A new modality of drug targeting to tumors has been proposed. The ligand-mediated approach, that ... more A new modality of drug targeting to tumors has been proposed. The ligand-mediated approach, that already increases the therapeutic index of the drug, can still be optimized by the encapsulation of the drug into sonosensitive nanoparticles. In this work, an endogenous ligand, estrone, was used to synthesize doxorubicin-encapsulating liposomes for estrogen receptor (ER)-positive breast cancer therapy with cyanuric chloride (2,4,6 trichloro-1,3,5 triazine) being used as a linking molecule to attach 3-OH group of estrone to the surface of liposomes. Then, drug release from liposomes was studied using ultrasound waves as a triggering mechanism with different frequencies and power densities. In addition, drug uptake by two cell lines ER-positive (MCF-7) and ER-negative (MDA-MB-231) was assessed, with the former cell line being examined later to study the synergetic effect of the receptor mediator targeting and ultrasound trigger. The sizes of the liposomes loaded with calcein (as a doxoru...

Free Radical Res, 1999

The interactions between hydroxyl radical production and the composition of the epicarp cells ass... more The interactions between hydroxyl radical production and the composition of the epicarp cells associated with the dark stained tissues of mature fruits of Encore mandarin were investigated. Phosphatidylinositol content of the cells associated with dark stains was lower in unpitted tissues, whereas the concentration of phosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine did not vary significantly. In these pitted cells, protein content also showed a 1.59-fold increase. Additionally, the relative proportions of gin, thr, asp, glu and gly increased sharply, while ala and tyr decreased. The polypeptide patterns showed quantitative changes when samples of stained and unstained tissues were compared by SDS-PAGE electrophoresis. Qualitatively, the cells associated with pitted tissues revealed a new polypeptide band with an apparent mol. wt. of 50.4 kDa as well as the disappearance of another one of 10 kDa. Ethylene production in the dark stained tissues was lower than in unpitted tissues and these cells showed significant increases in membrane permeability, hydroxyl radical production, and lipid peroxidation. Furthermore, in these tissues the levels of the carotenoids increased significantly but levels of chlorophyll decreased. It was concluded that in the pitted tissues the significant changes of the membrane composition are closely associated with an increasing acyl lipid peroxidation mediated by hydroxyl radical production. The modulation of this metabolism further indicates an incomplete degradation of fatty acids. The implications of the increasing accumulation of carotenoids in the synthesis of oxy radicals are also discussed.

Handbook of Ultrasonics and Sonochemistry, 2015

Nanocarriers are heavily researched as drug delivery vehicles capable of sequestering anti-neopla... more Nanocarriers are heavily researched as drug delivery vehicles capable of sequestering anti-neoplastic agents and then releasing their contents at the desired location. The feasibility of using such carriers stems from their ability to produce a multimodel delivery system whereby passive, ligand and triggered targeting can be applied in the fight against cancer. Passive targeting capitalizes on the leaky nature of tumor tissue which allows for the extravasation of particles with a size smaller than 0.5 m into the tumors. Ligand targeting utilizes the concept of receptor-mediated endocytosis and involves the conjugation of ligands onto the surface of nanoparticles, while triggered targeting involves the use of external and internal stimuli to release the carriers contents upon reaching the diseased location. In this review, micelles and liposomes have been considered due to the promising results they have shown in vivo and in vitro and their potential for advancements into clinical tr...

Annals of Botany, 1999

‘Peel pitting’ in the flavedo (the coloured epicarp) of ‘Encore’ mandarin arises as chlorotic spo... more ‘Peel pitting’ in the flavedo (the coloured epicarp) of ‘Encore’ mandarin arises as chlorotic spots. These spots correspond to parenchymal flattening and collapse of a variable number of sub-epidermal cell layers, which increase in parallel with the epidermis, extending between apparently healthy zones. The first signs of cellular damage are associated with internal membrane disorganization of the plastids. Great vesiculation

Radiation Protection Dosimetry, 2005

Therapeutic Nuclear Medicine is rapidly developing as an additional modality in Oncology. Direct ... more Therapeutic Nuclear Medicine is rapidly developing as an additional modality in Oncology. Direct treatment in the cancer cell with the use of biological vectors and appropriate radionuclides is highly desirable. A wide variety of specific tumour seeking radiopharmaceuticals are subject of current interest in clinical applications 1 . The radionuclides and the synthetic strategies used for radiolabelling the biomolecule are critical issues in the development of therapeutic radiopharmaceuticals. The treatment of bulk tumours by radionuclides that emit energetic alpha or beta particles is the preferred approach. However for the eradication of small clusters of cancer cells or small tumour nests, radionuclides that emit Auger electrons are considered to be advantageous because of their high level of cytoxicity and short-range biological effectiveness 2 . The development of effective radiotherapeutic specific compounds that target the disease site requires the design and synthesis of bifunctional ligands that could both stabilise a metallic centre and also allow the binding to a specific biomolecule 3 . Bifunctional ligands that stabilise the metallic centre and allow the simultaneous attachment of a tumour seeking molecule and a DNA intercalator are required for an effective radiotherapy based on Auger emitters. By including a DNA intercalator into the chelator framework, we expect to induce more efficient and selective damage to the DNA of cancer cells 4 . We report on chemical, radiochemical and biological studies of 153 Sm and 166 Ho complexes with macrocyclic polyamines DOTA, TRITA and TETA as well as on 99m Tc complexes with acyclic polyamines bearing a DNA intercalating fragment.

Journal of Organometallic Chemistry, 2004

The novel pyrazolyl containing ligands 4-(HOOC)pz(CH 2 ) 2 NH(CH 2 ) 2 NH 2 (L 1 ) and 4-(HOOCCH ... more The novel pyrazolyl containing ligands 4-(HOOC)pz(CH 2 ) 2 NH(CH 2 ) 2 NH 2 (L 1 ) and 4-(HOOCCH 2 )-3,5-Me 2 pz(CH 2 ) 2 NH-(CH 2 ) 2 NH 2 (L 2 ), and 3,5-Me 2 pz(CH 2 ) 2 S(CH 2 ) 2 SCH 2 CH 3 (L 3 ), 3,5-Me 2 pz(CH 2 ) 2 S(CH 2 ) 2 SCH 2 COOEt (L 4 ) and 3,5-Me 2 pz(CH 2 ) 2 S-(CH 2 ) 2 SCH 2 COOH (L 5 ) were synthesized, and their ability to stabilise complexes with the fac-[M(CO) 3 ] + (M = Re, 99m Tc) moiety was evaluated. Reactions of L 1 -L 5 with the Re(I) tricarbonyl starting materials (NEt 4 ) 2 [Re(CO) 3 Br 3 ] and/or [Re(CO) 5 Br] afforded complexes fac-[Re(CO) 3 (j 3 -L)] (L = L 1 -L 5 (1-5)), which contain the pyrazolyl ancillary ligands coordinated in a tridentate fashion. Complexes 1-5 were characterized by the common analytical techniques, which included single crystal X-ray diffraction analysis in the case of 4. The structural analysis of 4 confirmed the tridentate coordination mode of the pyrazole-dithioether ligand, which is facially coordinated to the Re(I) centre through the nitrogen from the pyrazole ring and the two thioether sulphur atoms, without involvement of the terminal ester functional group. The distorted octahedral coordination environment around the metal is completed by the three facial carbonyl ligands. The radioactive congeners of complexes 1, 3 and 4, fac-[ 99m Tc(CO) 3 (j 3 -L)] + (L = L 1 (1a), L 3 (3a), L 4 (4a)), have been prepared by reacting the precursor fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + with the corresponding ligands, and their identity confirmed by HPLC comparison with the rhenium surrogates. Complexes 1a and 3a have been challenged in the presence of a large excess of histidine or cysteine, in order to evaluate their in vitro stability. Only a negligible displacement was observed, indicating that pyrazole-diamine and pyrazole-dithioether chelators provide a high kinetic inertness and/or stability to organometallic complexes with the fac-[ 99m Tc(CO) 3 ] + moiety.

Fruits, 2001

Introduction. The fruit of 'Encore' mandarin (Citrus deliciosa × Citrus nobilis) usually shows ch... more Introduction. The fruit of 'Encore' mandarin (Citrus deliciosa × Citrus nobilis) usually shows chlorotic spots in the epicarp from the first stages of development. This peel disorder triggers off, thereafter, the occurrence of a large quantity of dark stains (pre-harvest 'peel pitting'). Materials and methods. A biochemical and ultra-structural study of the flavedo, using epicarp with and without stains, was carried out. Quality assays were assessed on the edible portion of the fruit or on juice. Results. The cell structure of pitted and unpitted epicarp analysed by electron microscopy revealed that dark spots were associated with the degradation of cellular membranes. The peroxidase system that shields the epicarp against photooxidative stress showed an inhibition of catalase activity and an increase of superoxide dismutase functioning. Moreover, the activities of ascorbate peroxidase and glutathione reductase remained unaffected in stained tissues. In sunshade trees, it was also found that the number of dark stains per fruit decreased but the internal quality of the endocarp was not significantly affected. The weight and the caliber of the fruit also slightly decreased. Discussion. High light intensities induce an oxidative stress in the epicarp, which is characterized by an increased peroxidation and degradation of biological membranes. On the other hand, protection against solar radiation alleviates the stress, but, although not affecting the internal quality of the fruit, slightly decreases the fruit weight and size.

Free Radical Research, 1999

The implications of the increasing accumulation of carotenoids in the synthesis of oxy radicals a... more The implications of the increasing accumulation of carotenoids in the synthesis of oxy radicals are also discussed.

Dalton Transactions, 2006

The novel pyrazolyl-based ligands 3,5-Me2pz(CH2)2NH(CH2)2NH(CH2)2NH2 and pz*(CH2)2NH-Gly-CH2STrit... more The novel pyrazolyl-based ligands 3,5-Me2pz(CH2)2NH(CH2)2NH(CH2)2NH2 and pz*(CH2)2NH-Gly-CH2STrit (pz*=pz, 3,5-Me2pz, 4-(EtOOC)CH(2)-3,5-Me2pz) were synthesized, and their suitability to stabilize Re(V) oxocomplexes was evaluated using different starting materials, namely (NBu4)[ReOCl4], [ReOCl3(PPh3)2] and trans-[ReO2(py)4]Cl. Compound reacts with trans-[ReO2(py)4]Cl yielding the cationic compound [ReO(OMe){3,5-Me2pz(CH2)2N(CH2)2NH(CH2)2NH2}](BPh4) in a low isolated yield. In contrast, the neutral complexes [ReO{pz*(CH2)2NH-Gly-CH2S}] (pz*=pz, 3,5-Me2pz, 4-(EtOOCCH2)-3,5-Me2pz) were synthesized almost quantitatively by reacting [ReOCl3(PPh3)2] or (NBu4)[ReOCl4] with the trityl-protected chelators. The X-ray diffraction analysis of and confirmed the tetradentate coordination mode of the respective ancillary ligands. In the monoanionic chelator coordinates to the metal through four nitrogen atoms, while in the chelator is trianionic, coordinating to the metal through three nitrogens and one sulfur atom. Solution NMR studies of , including two-dimensional NMR techniques (1H COSY and 1H/13C HSQC), confirmed that the N3S coordination mode of the chelators is retained in solution. Unlike , complexes may be considered relevant in the development of radiopharmaceuticals, as further corroborated by the synthesis of the congener [99mTcO{pz(CH2)2-NH-Gly-CH2S}]. This radioactive compound was obtained from 99mTcO4- in aqueous medium, in almost quantitative yield and with high specific activity and radiochemical purity.

ChemBioChem, 2008

cence spectroscopy titrations of L 1 and L 3 with CT DNA; Scatchard plot of the UV-visible spectr... more cence spectroscopy titrations of L 1 and L 3 with CT DNA; Scatchard plot of the UV-visible spectroscopy data for L 1 -L 4 , 7 and 9; McGhee-von Hippel binding isotherms for the fluorescence data of L 1 and L 2 .

Cancer Biotherapy & Radiopharmaceuticals, 2009

Different pyrazolyl-diamine ligands bearing anthracenyl or anthrapyrazole functionalities as DNA-... more Different pyrazolyl-diamine ligands bearing anthracenyl or anthrapyrazole functionalities as DNA-binding groups, at different positions of the chelator framework, were labeled with the fac-[(99m)Tc(CO)(3)](+) core. The resulting complexes, 1-4, are highly stable in vitro under physiologic conditions; all of them have been identified by high-performance liquid chromatography comparison with the Re congeners, with the exception of 3, that is anchored by an anthrapyrazole diamine ligand. Aiming to assess the ability of these complexes to target the cell nucleus and to induce enhanced cell death by effect of the Auger electrons emitted by (99m)Tc, the intracellular distribution and radiotoxicity of 1-4 were evaluated by using B16F1 murine melanoma cells. The radiotoxic effects depend very much on the position used to introduce the DNA-binding group and are well correlated with the nuclear uptake of the compounds. Complex 2, having the anthracenyl substituent at the 4-position of the pyrazolyl ring, rapidly entered the cells and accumulated inside the nucleus, exhibiting the highest radiotoxic effects. This compound induced an apoptotic cellular outcome, and its enhanced radiotoxic effects were certainly due to the Auger electrons emitted by the radiometal in close proximity to DNA.

Journal of Ethnopharmacology, 2004

Pterospartum tridentatum is a Leguminosae that grows spontaneously in Portugal. The flowers are u... more Pterospartum tridentatum is a Leguminosae that grows spontaneously in Portugal. The flowers are used in popular medicine for the treatment of throat irritation conditions and in herbal mixtures for diabetes. Diabetic vascular complications are due, among other reasons, to increased oxidative stress and for that reason antioxidants are believed to be beneficial for the diabetic patient. The flower water extract of this herbal drug showed dose-dependent protective effect of cultured human endothelial cells against oxidative injury induced by H 2 O 2 , at concentrations ≥0.3 mg/ml. This water extract, after liquid-liquid and chromatographic fractionation afforded one new isoflavone (5,5 -dihydroxy-3 -metoxi-isoflavone-7-O-␤-glucoside) and three other known isoflavones (prunetin, genistin and sissotrin). The structural characterisation of isolated compounds was achieved by UV, NMR and MS analysis. The flavonol glycoside isoquercitrin was also identified in the extract by HPLC analysis. Isoquercitrin is one of the active antioxidant principles of the extract since it showed dose-dependent protective effect against oxidative injury at concentrations ≥0.3 mM. Isoflavones were inactive at the same concentrations. The results suggest that the water extract of this herbal drug may prevent or reduce the development of diabetic vascular complications.