Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Design and Anticancer Properties of New Water-Soluble Ruthenium-Cyclopentadienyl Complexes.

Ruthenium complexes are emerging as one of the most promising classes of complexes for cancer therapy. However, their limited aqueous solubility may be the major limitation to their potential clinical application. In view and to contribute to the progress of this field, eight new water-soluble Ru(II) organometallic complexes of general formula [RuCp(mTPPMS)n(L)] [CF3SO3], where mTPPMS = diphenylphosphane-benzene-3-sulfonate, for n = 2, L is an imidazole-based ligand (imidazole, 1-benzylimidazole, 1-butylimidazole, (1-(3-aminopropyl)imidazole), and (1-(4-methoxyphenyl)imidazole)), and for n = 1, L is a bidentate heteroaromatic ligand (2-benzoylpyridine, (di(2-pyridyl)ketone), and (1,2-(2-pyridyl)benzo-[b]thiophene)) were synthesized and characterized. The new complexes were fully characterized by NMR, FT-IR, UV-vis., ESI-HRMS, and cyclic voltammetry, which confirmed all the proposed molecular structures. The antiproliferative potential of the new Ru(II) complexes was evaluated on MDAMB231 breast adenocarcinoma, A2780 ovarian carcinoma, and HT29 colorectal adenocarcinoma cell lines, showing micromolar (MDAMB231 and HT29) and submicromolar (A2780) IC50 values. The interaction of complex 6 with human serum albumin (HSA) and fatty-acid-free human serum albumin (HSAfaf) was evaluated by fluorescence spectroscopy techniques, and the results revealed that the ruthenium complex strongly quenches the intrinsic fluorescence of albumin in both cases.

Experimental data on novel Fe(III)-complexes containing phenanthroline derivatives for their anticancer properties.

This dataset is related to the research article entitled "May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?" [1]. It includes the characterization by UV-Vis absorption spectroscopy and magnetic techniques of a group of mixed ligand Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases (NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline), as well as [Fe(L)(EtOH)]NO3 (6), [Fe(phen)Cl3] (7) and [Fe(amphen)Cl3] (8). Data on their hydrolytic stability in physiological buffers is shown, as well as on their interaction with calf thymus DNA by spectroscopic tools. Additionally, the anticancer efficacy and the cellular death mechanisms activated in response to these drugs in HeLa, H1299 and MDA-MB-231 cells are provided.

May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.

Tracking antitumor metallodrugs: promising agents with the Ru(II)- and Fe(II)-cyclopentadienyl scaffolds.

Research on the field of metal complexes for the treatment of cancer diseases has attracted increasing interest due to the urgency in finding more efficient and selective treatments. Owing to their wide structural diversity, organometallic complexes appear as potential alternatives to the design of new anticancer candidates. Herein, we review recent progress in our work toward the development of new drugs based on Ru(II)- and Fe(II)-cyclopentadienyl scaffolds. Their design and chemical properties are reviewed and correlated with their biological effects, in particular the key role that coligands play in the overall behavior of the complex.

Mortalidad y readmisión en la unidad de cuidados intensivos / Mortality and readmission to the intensive care unit

Introducción: la readmisión en las unidades de cuidados intensivos durante la hospitalización se asocia con una significativa mortalidad y un incremento de la estadía y los costos, por lo que existe un creciente interés en identificar los elementos predictores de la readmisión. Objetivo: caracterizar las readmisiones y la mortalidad asociadas a factores de riesgo en la Unidad de Cuidados Intensivos Polivalente del Hospital Militar Central Dr. Carlos J. Finlay. Métodos: estudio descriptivo, longitudinal y retrospectivo, entre el 1ro. de enero al 31 de diciembre de 2008. La muestra estuvo constituida por todos los pacientes readmitidos en el periodo señalado. Se aplicó el estadígrafo t de Student para las variables edad, estadía hospitalaria al ingreso, readmisión o egreso. Resultados: predominaron los pacientes del sexo masculino mayores de 40 años. Hubo un 37,8 por ciento de mortalidad global, principalmente de fallecidos en entidades clínicas. Los pacientes con mayor período entre ingreso-readmisión, presentaron una elevada mortalidad. La sepsis respiratoria fue la causa más frecuente de readmisiones. La tasa de readmisión fue de 3,31 por ciento. Conclusión: la escala APACHE II constituyó un adecuado predictor de riesgo de morir en la Unidad de Cuidados Intensivos. Las variables con impacto sobre la mortalidad fueron edad, sexo masculino, ventilación mecánica y la presencia de enfermedades clínicas. La tasa de readmisiones se comportó por debajo de la media internacional, lo que evidencia un buen trabajo de la Unidad de Cuidados Intensivos en este indicador de calidad(AU)

Introduction: reentry to the ICU during hospitalization is associated with significant mortality and an increase of stay and costs, so that there is a growing interest in identifying predictors of readmission elements. Objective: to characterize reentries and mortality associated to risk factors in the Intensive Care Unit at Dr. Carlos J. Finlay Central Military Hospital. Methods: a descriptive, longitudinal and retrospective study was conducted from January 1st December to 31st 2008. The sample consisted of all patients readmitted within the given period. The Student t statistic for the variables such as age, hospital admission, hospital stay, hospital readmission or discharge was applied.Results: male patients over 40 years were in majority. There was 37.8 percent overall mortality, mainly of deaths in clinical entities. Patients with higher admission- readmission period showed a high mortality. Respiratory sepsis was the most frequent cause of readmissions. The readmission rate was 3.31 percent. Conclusion: APACHE II scale is an adequate predictor of risk of deceases in ICU. Variables with impact on mortality were age, male gender, mechanical ventilation, and the presence of clinical disease. The rate of readmissions was below the international average, which demonstrates good performance of ICU in this quality indicator(AU)

Mortalidad y readmisión en la unidad de cuidados intensivos / Mortality and readmission to the intensive care unit

INTRODUCCIÓN: la readmisión en las unidades de cuidados intensivos durante la hospitalización se asocia con una significativa mortalidad y un incremento de la estadía y los costos, por lo que existe un creciente interés en identificar los elementos predictores de la readmisión. OBJETIVO: caracterizar las readmisiones y la mortalidad asociadas a factores de riesgo en la Unidad de Cuidados Intensivos Polivalente del Hospital Militar Central "Dr. Carlos J. Finlay". MÉTODOS: estudio descriptivo, longitudinal y retrospectivo, entre el 1ro. de enero al 31 de diciembre de 2008. La muestra estuvo constituida por todos los pacientes readmitidos en el periodo señalado. Se aplicó el estadígrafo t de Student para las variables edad, estadía hospitalaria al ingreso, readmisión o egreso. RESULTADOS: predominaron los pacientes del sexo masculino mayores de 40 años. Hubo un 37,8 % de mortalidad global, principalmente de fallecidos en entidades clínicas. Los pacientes con mayor período entre ingreso-readmisión, presentaron una elevada mortalidad. La sepsis respiratoria fue la causa más frecuente de readmisiones. La tasa de readmisión fue de 3,31 %. CONCLUSIÓN: la escala APACHE II constituyó un adecuado predictor de riesgo de morir en la Unidad de Cuidados Intensivos. Las variables con impacto sobre la mortalidad fueron edad, sexo masculino, ventilación mecánica y la presencia de enfermedades clínicas. La tasa de readmisiones se comportó por debajo de la media internacional, lo que evidencia un buen trabajo de la Unidad de Cuidados Intensivos en este indicador de calidad.

INTRODUCTION: reentry to the ICU during hospitalization is associated with significant mortality and an increase of stay and costs, so that there is a growing interest in identifying predictors of readmission elements. OBJECTIVE: to characterize reentries and mortality associated to risk factors in the Intensive Care Unit at "Dr. Carlos J. Finlay" Central Military Hospital. METHODS: a descriptive, longitudinal and retrospective study was conducted from January 1st December to 31st 2008. The sample consisted of all patients readmitted within the given period. The Student t statistic for the variables such as age, hospital admission, hospital stay, hospital readmission or discharge was applied. RESULTS: male patients over 40 years were in majority. There was 37.8 % overall mortality, mainly of deaths in clinical entities. Patients with higher admission- readmission period showed a high mortality. Respiratory sepsis was the most frequent cause of readmissions. The readmission rate was 3.31 %. CONCLUSION: APACHE II scale is an adequate predictor of risk of deceases in ICU. Variables with impact on mortality were age, male gender, mechanical ventilation, and the presence of clinical disease. The rate of readmissions was below the international average, which demonstrates good performance of ICU in this quality indicator.

First polymer "ruthenium-cyclopentadienyl" complex as potential anticancer agent.

d-glucose end-capped polylactide ruthenium cyclopentadienyl complex (RuPMC) was newly synthesized by a straightforward method. RuPMC was tested against human MCF7 and MDAMB231 breast and A2780 ovarian adenocarcinoma revealing IC50 values in the micromolar range. A pH dependent hydrolysis is advanced by preliminary UV-visible spectroscopy. Cellular distribution studies showed that RuPMC is predominantly found in the nucleus and in the membrane. Data suggest potential application of RuPMC as a new drug delivery system for Ru(II)Cp compounds.

Cellular uptake mechanisms of an antitumor ruthenium compound: the endosomal/lysosomal system as a target for anticancer metal-based drugs.

Previous studies have described promising antitumor activity of an organometallic Ru(II) complex, η5-cyclopentadienyl(2,2'-bipyridyl)(triphenylphosphane) Ruthenium(II) triflate ([η5-C5H5)Ru(2,2'-bipyridyl)(PPh3)][CF3SO3]) herein designated as TM34. Its broad spectrum of activity against a panel of human tumor cell lines and high antiproliferative efficiency prompted us to focus on its mode of action. We present herein results obtained with two human tumor cell lines A2780 and MDAMB231 on the compound distribution within the cell, the mechanism of its activity, and its cellular targets. The prospective metallodrug TM34 revealed: (a) fast antiproliferative effects even at short incubation times for both cell lines; (b) preferential localization at the cell membrane and cytosol; (c) cellular activity by a temperature-dependent process, probably macropinocytosis; (d) inhibition of a lysosomal enzyme, acid phosphatase, in a dose-dependent mode; and (e) disruption and vesiculation of the Golgi apparatus, which suggest the involvement of the endosomal/lysosomal system in its mode of action. These results are essential to elucidate the basis for the cytotoxic activity and mechanism of action of this Ru(II)(η5-cyclopentadienyl) complex.

Crystal structure and experimental and theoretical studies of the second-order nonlinear optical properties of salts of triphenylguanidine with carboxylic acids.

N,N',N''-triphenylguanidinium carboxylate salts have been prepared by acid-base reactions of triphenylguanidine with formic, benzoic, and m-methoxybenzoic acids, and their single-crystal X-ray structure analysis has been performed. The salts were found to crystallize into noncentrosymmetric structures with an orthorhombic space group P2(1)2(1)2(1) for the formate and m-methoxybenzoate salts and a monoclinic space group Cc for the benzoate salt. The anions and cations are linked by intermolecular hydrogen bonds with the same motifs in the three salts. By using the molecular structures, the molecular first hyperpolarizabilities of several clusters were determined by semiempirical methods, and the components of the second-order susceptibility tensor, d, of triphenylguanidine and those of the reported crystals were evaluated using the oriented gas model with two different local-field corrections. The efficiency of the second-harmonic generation of triphenylguanidine and that of the reported triphenylguanidinium salts were measured using the Kurtz and Perry powder method.

Relação entre índice de resistência obtido pela ultra-sonografia Doppler transfortanela e o neurodesenvolvimento até o primeiro ano de vida em recém-nascidos a termo com encefalopatia hipóxico-isquêmica leve e moderada / Relation between the resistance index obtained by the transfontanellar Doppler ultrasonography and the neurological development until the first year of life in term infants with mild or moderate hypoxic-ischaemic encephalopathy

OBJETIVO: Avaliar a relação do índice de resistência (IR) obtido pela ultra-sonografia Doppler transfontanela com o neurodesenvolvimento até um ano de idade, em recém-nascidos (RN) a termo com encefalopatia hipóxica-isquêmica (EHI) leve a moderada, secundária à asfixia intra-parto. MÉTODO: Estudo prospectivo em 20 RN com EHI leve a moderada, IR elevado no primeiro exame de Doppler, e sem doenças associadas ou anormalidades morfológicas cerebrais. Foram realizados exames seriados bimensais de Doppler transfontanela a partir do sétimo dia de vida, e avaliações clínicas mensais do neurodesenvolvimento no primeiro ano de vida. RESULTADOS: Houve normalização progressiva dos valores de IR até o último exame realizado. Cinco pacientes apresentaram normalização clínico-neurológica no período neonatal, após o primeiro exame de Doppler. Quinze lactentes apresentaram alterações neurológicas com resolução a partir do segundo trimestre de vida. CONCLUSÃO: Houve relação entre os períodos em que ocorreu a normalização dos valores de IR e a melhora clínica-neurológica.

OBJECTIVE: To evaluate the relation between the resistance index (RI) obtained by transfontanellar Doppler ultrasonography, and the neurodevelopment until one year of life, at term newborns with mild or moderate hypoxic-ischaemic encephalopathy due to intrapartum asphyxia. METHOD: 20 term newborns, with mild or moderate hypoxic-ischemic encephalopathy, high values of resistance index in the first exam, and without cerebral morfologic abnormalities or other diseases. They were submitted to serial bimonthly transfontanellar Doppler ultrasonography, from the seventh day of life on, and monthly clinical neurodevelopment assessment until one year of life. RESULTS: There was a progressive normalization of RI values until the last examination. In five cases there were clinical neurologic normalization in the neonatal period after the first Doppler exam. Fifteen infants presented neurologic abnormalities, with normalization after the second trimester of life. CONCLUSION: There was a relation between the normal RI values with the normalization of the clinical assessment.

Utilizaçäo de recurso tecnológico como agente facilitador do trabalho de enfermagem / The utilization of technological resources as a facilitator agent for nursing work

Atualmente recursos tecnológicos vêm sendo empregados no sentido de facilitar a execuçäo de diversas atividades laborais, entre eles encontra-se o elevador de pacientes impossibilitados, cujo uso visa evitar o desgaste físico ao trabalhador de enfermagem. Os objetivos deste estudo foram averiguar o motivo da näo utilizaçäo de tal recurso disponível em uma clínica de neurologia e elaborar um roteiro de orientaçäo e treinamento para sua utilizaçäo...