Modulation of fibronectin and laminin expression by Rhodium (II) citrate-coated maghemite nanoparticles in mice bearing breast tumor.

Degradation of cellular matrix is one of the important processes related to the progression of breast cancer. Tumor cells have the ability to exhibit necessary conditions for growth and survival, promoting degradation processes of extracellular matrix proteins, such as laminin (LN) and fibronectin (FN). In this study, we evaluated whether treatments, based on free rhodium (II) citrate (Rh2(H2cit)4), maghemite nanoparticles coated with citrate (Magh-cit) and maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2(H2cit)4), in murine metastatic breast carcinoma models can modulate the expression of laminin and fibronectin proteins. Synthesized nanoparticles were characterized using X-ray diffraction, transmission electron microscopy, energy dispersive spectroscopy and dynamic light scattering. The expression of FN and LN was assessed using immunohistochemistry and western blotting. The gene expression of FN1 and LAMA1 were evaluated using real-time PCR. The FN1 and LAMA1 transcripts from the Magh-Rh2(H2cit)4 treated group were 95% and 94%, respectively, lower than the control group. Significant reduction in tumor volume for animals treated with Magh-Rh2(H2cit)4 was observed, of about 83%. We witnessed statistically significant reductions of FN and LN expression following treatment with Magh-Rh2(H2cit)4. We have demonstrated that the antitumor effects of Magh-Rh2(H2cit)4 and Rh2(H2cit)4 regulate the expression of FN and LN in metastatic breast tumors.

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.

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

BACKGROUND: Magnetic 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. METHODS: Mice 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. RESULTS: Regarding 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. CONCLUSIONS: In 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.

Electrochemical evaluation of rhodium dimer-DNA interactions.

The interaction of rhodium dimers, including the carboxylates (acetate, propionate, butyrate, trifluoroacetate, citrate and gluconate), amidates (acetamidate and trifluoroacetamidate) and carboxamidate (Doyle catalyst S) with DNA was investigated by electrochemical methods. Differential pulse voltammetry measurements showed, in agreement to literature data, that most of rhodium carboxylates have a higher affinity for adenine than guanine residues. Some differences of reactivity may be correlated with the compound structures and these were helpful in understanding the influence of equatorial ligands on axial coordination mechanisms. The preliminary results might be extended for further studies on quantitative structure activity relationship approaches, highlighting electrochemical methods as a tool for this purpose.

Water-soluble rhodium(II) carboxylate adducts: cytotoxicity of the new compounds.

Rhodium(II) carboxylate (acetate, propionate, and butyrate) adducts with isonicotinic acid (Hisonic) were prepared for study. Elemental analyses and electronic spectroscopy show that the adducts contain two isonicotinic acid ligands coordinated in the axial position at the pyridinic nitrogen. The in vitro (K562 human leukemic cell line) assay and LD10 in mice results, in addition to tests of solubility, suggest that, in the presence of blood lipids or cellular membrane, the adducts dissociate into the parent compounds and the rhodium(II) carboxylate enters the cell to carry out its biological effects.

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors.

Rhodium (II) trifluoroacetate (TFARh), rhodium (II) trifluoroacetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 mumol/kg (40-70 and 59 mg/kg, respectively), these compounds had no toxic effects up to 14 days. At ip doses of 10 mumol kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 microM significantly increased the number of dead cells in cultured Ehrlich tumor cells.

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors

Rhodium (II) trifluoracetate (TFARh), rhodium (II) trifluoracetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 µmg/kg (40-70 and 59 mg/kg, respectively), these coumpounds had no toxic effects up to 14 days. At ip doses of 10 µmol Kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 µM significantly increased the number of dead cells in cultured Ehrlich tumor cells

Adducts of nitroimidazole derivatives with rhodium(II) carboxylates: syntheses, characterization, and evaluation of antichagasic activities.

Adducts of several rhodium(II) carboxylates with two antiparasitic nitroimidazole ligands were prepared and characterized by elemental microanalysis, thermogravimetry, spectrophotometry (IR, UV, and visible), and proton magnetic resonance. Results of elemental and thermogravimetric analyses were consistent with the general formula Rh2(RCOO)4. 2L (R = aliphatic or aromatic carboxylic groups; L = metronidazole or benznidazole). The reddish-brown color of the adducts as well as their visible spectra suggest axial coordination of the nitroimidazole ligands through nitrogen atoms. NMR spectra indicate N3 as the coordinating atoms. Screening tests performed on cultures of T. cruzi indicate that aliphatic complexes--particularly propionate and acetate adducts--were more active than their aromatic counterparts, the same being observed with benznidazole adducts in relation to their metronidazole analogues. Evaluated for their usefulness as transfusion prophylactic agents against Chagas' disease, propionate derivatives failed to sterilize T. cruzi infected blood. An oral toxicity assay in mice showed mild toxic effects with daily doses of 5 mg/kg for 20 days.

Antitumor effects of rhodium (II) citrate in mice bearing Ehrlich tumors.

Rhodium II citrate was tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and inhibition of DNA synthesis by Ehrlich tumor, malignant adrenocortical cells (Y-1) and normal adrenocortical cells (AR-1). At ip doses up to 260 mg/kg, the compound had no toxic effects for up to 14 days. The same total dose given over 4 days significantly increased the survival rate of mice bearing Ehrlich ascites cells. Thymidine incorporation by Ehrlich tumor, Y-1 and AR-1 cells in vitro was inhibited 50% by 0.1 to 0.2 mM concentrations of the compound. We conclude that the increased survival of the tumor-bearing mice was due at least in part to the inhibition of DNA synthesis with a consequent reduction of cell division and tumor growth.

Antitumor effects of Rhodium (II) citrate in mice bearing Chrlich tumors

Rhodium II citrate was tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and inhibition of DNA synthesis by Ehrlich tumor, malignant adrenocortical cells (Y-1) and normal adrenocortical cells (AR-1)_. At ip doses up to 260 mg/Kg, the compound had no toxic effects for up to 14 days. The same total dose given over 4 days significantly increased the survial rat of mice bearing Ehrlich ascites cells. Thymidine incorporation by Ehrlkich tumor, Y-1 cells in vitro was inhibited 50% by a.1 to 0.2 mM concentrations of the compound. We conclude that the increase survival of the tumor-bearing mice was due at least in part to the inhibition of DNA synthesis with a consequet reduction of cell division and tumor growth