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

Abstract Background Rhodium (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 former's 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. Results Treatment 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. Conclusions The 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.

A mathematical model of regional citrate anticoagulation in hemodialysis

Regional citrate anticoagulation (RCA) during hemodialysis (HD) has several advantages over heparin anticoagulation, but calcium (Ca) derangements are a major concern necessitating repeated monitoring of systemic ionized Ca (Ca(2+)). We developed a mathematical model of Ca and citrate (Ci) kinetics during RCA.

Variability in urinary oxalate measurements between six international laboratories

Hyperoxaluria is a major risk factor for kidney stone formation. Although urinary oxalate measurement is part of all basic stone risk assessment, there is no standardized method for this measurement.

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria

The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.

Arterial stiffness depends on serum ionized calcium levels during dialysis with regional citrate anticoagulation

Hemodynamic effects related to changes in serum ionized calcium (iCa) are difficult to determine during conventional hemodialysis (HD) using a fixed dialysate concentration of calcium. Regional citrate anticoagulation (RCA) allows the study of the effects of predefined iCa changes on arterial stiffness and blood pressure (BP) during a single dialysis session. In a crossover study, 15 patients with end-stage renal disease underwent two HD sessions with RCA. Each session was divided into two study phases in which iCa was titrated either to 0.8-1.0 mm or to 1.1-1.4 mm. The sequence of phases was randomly chosen and alternated for the second session. After reaching a stable iCa level, pulse wave velocity (PWV), arterial BP, and heart rate were measured. iCa levels were modified during sequence 1 (iCa low-high) from a predialysis baseline value of 1.15 ± 0.09 mm, first to 0.92 ± 0.05 mm (time point 1; P < 0.001 vs. baseline) and then to 1.18 ± 0.05 (time point 2; ns). During sequence 2 (iCa high-low), iCa levels were modified from 1.15 ± 0.12 mm first to 1.20 ± 0.05 mm (time point 1; ns vs. baseline) and then to 0.93 ± 0.03 (time point 2; P < 0.001). Assuming a basic linear repeated measures model, PWV was positively related to iCa levels (P < 0.03) independent of systolic or diastolic BP, heart rate, or ultrafiltration rate. PWV is closely related to acute changes in serum iCa levels in HD patients using RCA. RCA provides an interesting opportunity to study the effects of acute iCa changes during one dialysis procedure.

Taurolidine-citrate lock solution (TauroLock) significantly reduces CVAD-associated grampositive infections in pediatric cancer patients

BACKGROUND: Taurolidin/Citrate (TauroLock), a lock solution with broad spectrum antimicrobial activity, may prevent bloodstream infection (BSI) due to coagulase-negative staphylococci (CoNS or 'MRSE' in case of methicillin-resistant isolates) in pediatric cancer patients with a long term central venous access device (CVAD, Port- or/Broviac-/Hickman-catheter type). METHODS: In a single center prospective 48-months cohort study we compared all patients receiving anticancer chemotherapy from April 2003 to March 2005 (group 1, heparin lock with 200 IU/ml sterile normal saline 0.9%; Canusal Wockhardt UK Ltd, Wrexham, Wales) and all patients from April 2005 to March 2007 (group 2; taurolidine 1.35%/Sodium Citrate 4%; TauroLock, Tauropharm, Waldbüttelbrunn, Germany). RESULTS: In group 1 (heparin), 90 patients had 98 CVAD in use during the surveillance period. 14 of 30 (47%) BSI were 'primary Gram positive BSI due to CoNS (n = 4) or MRSE (n = 10)' [incidence density (ID); 2.30 per 1000 inpatient CVAD-utilization days].In group 2 (TauroLock), 89 patients had 95 CVAD in use during the surveillance period. 3 of 25 (12%) BSI were caused by CoNS. (ID, 0.45). The difference in the ID between the two groups was statistically significant (P = 0.004). CONCLUSION: The use of Taurolidin/Citrate (TauroLock) significantly reduced the number and incidence density of primary catheter-associated BSI due to CoNS and MRSE in pediatric cancer patients.

Citrate- vs. acetate-based dialysate in bicarbonate haemodialysis: consequences on haemodynamics, coagulation, acid-base status, and electrolytes

BACKGROUND: A concentrate for bicarbonate haemodialysis acidified with citrate instead of acetate has been marketed in recent years. The small amount of citrate used (one-fifth of the concentration adopted in regional anticoagulation) protects against intradialyser clotting while minimally affecting the calcium concentration. The aim of this study was to compare the impact of citrate- and acetate-based dialysates on systemic haemodynamics, coagulation, acid-base status, calcium balance and dialysis efficiency. METHODS: In 25 patients who underwent a total of 375 dialysis sessions, an acetate dialysate (A) was compared with a citrate dialysate with (C+) or without (C) calcium supplementation (0.25 mmol/L) in a randomised single-blind cross-over study. Systemic haemodynamics were evaluated using pulse-wave analysis. Coagulation, acid-base status, calcium balance and dialysis efficiency were assessed using standard biochemical markers. RESULTS: Patients receiving the citrate dialysate had significantly lower systolic blood pressure (BP) (-4.3 mmHg, p < 0.01) and peripheral resistances (PR) (-51 dyne.sec.cm-5, p < 0.001) while stroke volume was not increased. In hypertensive patients there was a substantial reduction in BP (-7.8 mmHg, p < 0.01). With the C+ dialysate the BP gap was less pronounced but the reduction in PR was even greater (-226 dyne.sec.cm-5, p < 0.001). Analyses of the fluctuations in PR and of subjective tolerance suggested improved haemodynamic stability with the citrate dialysate. Furthermore, an increase in pre-dialysis bicarbonate and a decrease in pre-dialysis BUN, post-dialysis phosphate and ionised calcium were noted. Systemic coagulation activation was not influenced by citrate. CONCLUSION: The positive impact on dialysis efficiency, acid-base status and haemodynamics, as well as the subjective tolerance, together indicate that citrate dialysate can significantly contribute to improving haemodialysis in selected patients.

Correlation between Accurate Electron Density and Linear Optical Properties in Amino Acid Derivatives: L-Histidinium Hydrogen Oxalate

The accurate electron density and linear optical properties of L-histidinium hydrogen oxalate are discussed. Two high-resolution single crystal X-ray diffraction experiments were performed and compared with density functional calculations in the solid state as well as in the gas phase. The crystal packing and the hydrogen bond network are accurately investigated using topological analysis based on quantum theory of atoms in molecules, Hirshfeld surface analysis, and electrostatic potential mapping. The refractive indices are computed from couple perturbed Kohn-Sham calculations and measured experimentally. Moreover, distributed atomic polarizabilities are used to analyze the origin of the linear susceptibility in the crystal, in order to separate molecular and intermolecular causes. The optical properties are also correlated with the electron density distribution. This compound also offers the possibility to test the electron density building block approach for material science and different refinement schemes for accurate positions and displacement parameters of hydrogen atoms, in the absence of neutron diffraction data.

Chiral Templating Activity of Tris(bipyridine)ruthenium(II) Cation in the Design of Three-Dimensional (3D) Optically Active Oxalate-Bridged {[Ru(bpy) 3 ][Cu 2 x Ni 2(1 - x ) (C 2 O 4 ) 3 ]} n (0 ≤ x ≤ 1; bpy = 2,2‘-bipyridine): Structural, Optical, and Magnetic Studies

Three-dimensional oxalate-based {[Ru(bpy)3][Cu2xNi2(1-x)(ox)3]}n (0≤ x ≤ 1, ox = C2O42-, bpy = 2,2‘bipyridine) were synthesized. The structure was determined for x = 1 by X-ray diffraction on single crystal. The compound crystallizes in the cubic space group P4132. It shows a three-dimensional 10-gon 3-connected (10,3) anionic network where copper(II) has an unusual tris(bischelated) environment. X-ray powder diffraction patterns and their Rietveld refinement show that all the compounds along the series are isostructural and single-phased. According to X-ray absorption spectroscopy, copper(II) and nickel(II) have an octahedral environment, respectively elongated and trigonally distorted. As shown by natural circular dichroism, the optically active forms of {[Ru(bpy)3][CuxNi2(1-x)(ox)3]}n are obtained starting from resolved Δ- or Λ-[Ru(bpy)3]2+. The Curie−Weiss temperatures range between −55 (x = 1) and −150 K (x = 0). The antiferromagnetic exchange interaction thus decreases when the copper contents increases in agreement with the crystallographic structure of the compounds and the electronic structure of the metal ions. At low temperature, the compounds exhibit complex long-range ordered magnetic behavior.

Polyfunctional Two- (2D) and Three- (3D) Dimensional Oxalate Bridged Bimetallic Magnets

We report major results concerning polyfunctional two- (2D) and three- (3D) dimensional oxalate bridged bimetallic magnets. As a consequence of their specific organisation they are composed of an anionic sub-lattice and a cationic counter-part. These bimetallic polymers can accommodate various counter-cations possessing specific physical properties in addition to the magnetic ones resulting from the interactions between the metallic ions in the anionic sub-lattice. Thus, molecular magnets possessing paramagnetic, conductive and optical properties are presented in this review.