Aparecido Ribeiro de Souza

Bismuth nitrate pentahydrate: a new and environmentally benign reagent for guanidylation of N-benzoylthioureas

The bismuth nitrate-mediated guanidylation of N-benzoylthioureas was studied. This salt proved to be an effective guanylating reagent and allowed the obtention of N-benzoyl-guanidines in good yields. The methodology described is a promising alternative to the use of toxic HgCl2 in the synthesis of polysubstituted guanidines.

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

BackgroundMagnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma.MethodsMice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry.ResultsRegarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining.ConclusionsIn summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications.

Free Rhodium (II) citrate and rhodium (II) citrate magnetic carriers as potential strategies for breast cancer therapy

BackgroundRhodium (II) citrate (Rh2(H2cit)4) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates Rh2(H2cit)4 as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh2(H2cit)4 and SPIOs can represent a strategy to enhance the formers therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh2(H2cit)4) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures.ResultsTreatment with free Rh2(H2cit)4 induced cytotoxicity that was dependent on dose, time, and cell line. The IC50 values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 μM Rh2(H2cit)4-loaded maghemite nanoparticles (Magh-Rh2(H2cit)4) and Rh2(H2cit)4-loaded magnetoliposomes (Lip-Magh-Rh2(H2cit)4) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh2(H2cit)4, were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh2(H2cit)4 induces cell death by apoptosis.ConclusionsThe treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh2(H2cit)4 treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh2(H2cit)4 delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.

Rh2(CF3CONH)4: The First Biological Assays of a Rhodium (II) Amidate

The rhodium (II) complexes Rh2(tfa)4.2(tfac) and Rh2(tfacam)4 (tfacam = CF3CONH-,tfa = CF3COO-,tfac = CF3CONH2) were synthesized and characterized by microanalysis and electronic and vibrational spectroscopies. Rh2(tfacam)4 was tested both in vitro (U937 and K562 human leukemia cells and Ehrlich ascitic tumor cells) and in vivo for cytostatic activity and lethal dose determination, respectively. This is the first rhodium tetra-amidate to have its biological activity evaluated. The LD50 value for Rh2(tfacam)4 is of the same order as that of cisplatin, and it was verified that the rhodium complex usually needs lower doses than cisplatin to promote the same inhibitory effects.

Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay

Breast cancer is one of the most prevalent cancer types among women. The use of magnetic fluids for specific delivery of drugs represents an attractive platform for chemotherapy. In our previous studies, it was demonstrated that maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2Cit) induced in vitro cytotoxicity and in vivo antitumor activity, followed by intratumoral administration in breast carcinoma cells. In this study, our aim was to follow intravenous treatment to evaluate the systemic antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Female Balb/c mice were evaluated with regard to toxicity of intravenous treatments through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine and liver, kidney, and lung histology. The antitumor activity of rhodium (II) citrate (Rh2Cit), Magh-Rh2Cit, and maghemite nanoparticles coated with citrate (Magh-Cit), used as control, was evaluated by tumor volume reduction, histology, and morphometric analysis. Magh-Rh2Cit and Magh-Cit promoted a significant decrease in tumor area, and no experimental groups presented hematotoxic effects or increased levels of serum ALT and creatinine. This observation was corroborated by the histopathological examination of the liver and kidney of mice. Furthermore, the presence of nanoparticles was verified in lung tissue with no morphological changes, supporting the idea that our nanoformulations did not induce toxicity effects. No studies about the systemic action of rhodium (II) citrate-loaded maghemite nanoparticles have been carried out, making this report a suitable starting point for exploring the therapeutic potential of these compounds in treating breast cancer.

Aspectos técnicos e legais do gerenciamento de resíduos químico-farmacêuticos

The environmental risks from waste production has arisen with the technological progress, as well as with the world population increase. The risks from the industrial or academic routines in pharmaceutical or fine chemical plants and projects are remarkable. For this reason, many projects focusing on the optimization of waste treatment in these places have been proposed. This paper, reviews some of the main strategies introduced, in order to solve or decrease the problems, in the management of pharmaceutical-chemical wastes in industry, universities, among other potential kind of waste generators. The main regulatory and technical aspects, associated to segregation, packaging, treatment and final disposal of these wastes are presented.

Acute and subchronic toxicity of the antitumor agent rhodium (II) citrate in Balb/c mice after intraperitoneal administration

This study aimed to investigate potential acute and subchronic toxicity of rhodium (II) citrate in female Balb/c mice after intraperitoneal injections. In the acute test, independent groups received five doses; the highest dose (107.5 mg/kg) was equivalent to 33 times that used in our previous reports. The other doses were chosen as proportions of the highest, being 80.7 (75%), 53.8 (50%), 26.9 (25%) or 13.8 mg/kg (12.5%). Animals were monitored over 38 days and no severe signs of toxicity were observed, according to mortality, monitoring of adverse symptoms, hematological, biochemical and genotoxic parameters. We conclude that the median lethal dose (LD50) could be greater than 107.5 mg/kg. In the subchronic test, five doses of Rh2Cit (80, 60, 40, 20 or 10 mg/kg) were evaluated and injections were conducted on alternate days, totaling five applications per animal. Paclitaxel (57.5 mg/kg) and saline solution were controls. Clinical observations, histopathology of liver, lung and kidneys and effects on hematological, biochemistry and genotoxic records indicated that Rh2Cit induced no severe toxic effects, even at an accumulated dose up to 400 mg/kg.We suggest Rh2Cit has great potential as an antitumor drug without presenting acute and subchronic toxicity.

Efficient Enzyme-Free Biomimetic Sensors for Natural Phenol Detection.

The development of sensors and biosensors based on copper enzymes and/or copper oxides for phenol sensing is disclosed in this work. The electrochemical properties were studied by cyclic and differential pulse voltammetry using standard solutions of potassium ferrocyanide, phosphate/acetate buffers and representative natural phenols in a wide pH range (3.0 to 9.0). Among the natural phenols herein investigated, the highest sensitivity was observed for rutin, a powerful antioxidant widespread in functional foods and ubiquitous in the plant kingdom. The calibration curve for rutin performed at optimum pH (7.0) was linear in a broad concentration range, 1 to 120 µM (r = 0.99), showing detection limits of 0.4 µM. The optimized biomimetic sensor was also applied in total phenol determination in natural samples, exhibiting higher stability and sensitivity as well as distinct selectivity for antioxidant compounds.

Distribution of Rhodium in Mice Submitted to Treatment With the Adduct of Rhodium Propionate and Sodium Isonicotinate

The distribution of rhodium in Balb/c mice following intraperitoneal (ip) administration of a solution of adduct of rhodium propionate and sodium isonicotinate has been investigated. The metal concentration was determined in blood and in the following organ tissues: brain, heart, lung, liver, spleen, kidney, testes, and uterus/ovary, and the rhodium concentration was obtained by Inductively Coupled Argon Atomic Emission Spectroscopy (ICP-AES). The metal was detected in all organ tissues examined, mainly in spleen, liver, uterus/ovary and heart. Nine days after the injection, traces of rhodium were found in the liver and kidneys and, twenty days after the injection, only in the liver.

Development of a Promising Antitumor Compound Based on Rhodium(II) Succinate Associated with Iron Oxide Nanoparticles Coated with Lauric Acid/Albumin Hybrid: Synthesis, Colloidal Stability and Cytotoxic Effect in Breast Carcinoma Cells

In this study, we report the synthesis and characterization of a new rhodium(II) succinate complex (Rh2(suc)4) and its immobilization on lauric acid bilayer-coated maghemite nanoparticles (MGH-2L/Rh2(suc)4) and subsequent adsorption with bovine serum albumin (MGH-2L/Rh2(suc)4/BSA). Rh2(suc)4 has been characterized by elemental analysis, potentiometric titration, TGA, MS, FTIR and UV-Vis analysis. The maghemite phase was confirmed by XRD, and a diameter of 10 nm was obtained by Sherrer equation. The VSM experiment showed superparamagnetic properties. TEM showed nanoparticles with a spherical shape and a mean diameter of 8.5±0.4 and 9.1 ± 0.4 nm for MGH-2L/Rh2(suc)4 and MGH-2L/Rh2(suc)4/BSA, respectively. FTIR and TGA confirmed the immobilization of Rh2(suc)4 and bovine serum albumin adsorption on superparamagnetic iron oxide. Hydrodynamic size (DH) and zeta potential (ζ) measurements were made in aqueous, NaCl and DMEM media. DH for dispersions was lower in aqueous medium, but increased in saline and DMEM media. In aqueous and saline media, ζ was not altered for MGH-2L and MGH-2L/Rh2(suc)4, but was significantly lower for MGH-2L/Rh2(suc)4/BSA. Therefore, MGH-2L/Rh2(suc)4/BSA was the most stable dispersion, meaning that BSA coating prevents aggregation more than lauric acid bilayer coating. MGH-2L/Rh2(suc)4 and MGH-2L/Rh2(suc)4/BSA dispersions induced cytotoxicity in breast carcinoma (MCF-7) and fibroblast cells in culture, and this effect was higher than that exerted by free Rh2(suc)4 and more specific to breast carcinoma cells than to fibroblasts. Therefore, we suggest that these dispersions have an important potential for future clinical applications and, thus, they should be considered a platform to enhance Rh2(suc)4 cytotoxicity, specifically in breast carcinoma.