Lymph Node Metastases Detection Using Gd2O3@PCD as Novel Multifunctional Contrast Imaging Agent in Metabolic Magnetic Resonance Molecular Imaging.

Axillary lymph node detection is crucial to staging and prognosis of the lymph node metastatic spread in breast cancer. Currently, lymphoscintigraphy and blue dye, as the conventional methods to localize sentinel lymph nodes (SLNs), are invasive and can only be performed during surgery. This study has had a novel hybrid gadolinium oxide nanoparticle coating with Cyclodextrin-based polyester as a high-relaxivity T1 magnetic resonance molecular imaging (MRMI) contrast agent (CA). Twelve female BALB/c mice were randomly divided into three groups of four mice; each group was injected with 4T1 cells to obtain metastasis lymph nodes and diagnosed by using the 3D T1W (VIBE) MRI (Siemens 3T, Prisma). The synthesized Gd2O3@PCD nanoparticles with a suitable particle size range of 20-40 nm have had much higher longitudinal relaxivity (r 1) for Gd2O3@PCD and Gd-DOTA (Dotarem) with the values of 3.98 mM-1·s-1 ± 0.003 and 2.71 mM-1·s-1 ± 0.005, respectively. Identical MR images in coronal views were subsequently obtained to create time-intensity curves of the right axillary lymph nodes and to measure the contrast ratio (CR). The peak CR and qualitative assessment of axillary lymph nodes at five-time points were evaluated. After subcutaneous injection, the contrast ratio of axillary lymph node and tumor in mice exhibited CR peak of Gd2O3@PCD and Dotarem with the values of 2.21 ± 0.06 and 0.40 ± 0.004 for lymph node and 2.54 ± 0.04 and 1.21 ± 0.007 for the tumor, respectively. Furthermore, the lumbar-aortic lymph node is weakly visible in the original coronal image. In conclusion, the use of Gd2O3@PCD nanoparticles as novel MRMI CAs enables high resolution for the detection of lymph node metastasis in mice with the potential capability for breast cancer diagnostic imaging.

Dosimetry and Radioenhancement Comparison of Gold Nanoparticles in Kilovoltage and Megavoltage Radiotherapy using MAGAT Polymer Gel Dosimeter.

BACKGROUND: Numerous unique characteristics of the nanosized gold, including high atomic number, low toxicity, and high biocompatibility make it one of the most appropriate nanostructures to boost radiotherapy efficacy. Many in-vivo and in-vitro investigations have indicated that gold nanoparticles (AuNPs) can significantly increase tumor injuries in low kilovoltage radiotherapy. While deep-lying tumors require much higher energy levels with greater penetration power, and investigations carried out in megavoltage energy range show contradictory results. OBJECTIVE: In this study, we quantitatively assess and compare dose enhancement factors (DEFs) obtained through AuNPs under radiation of Cobalt-60 source (1.25MeV) versus Iridium-192 source (380 KeV) using MAGAT gel dosimeter. MATERIAL AND METHODS: MAGAT polymer gel in both pure and combined with 0.2 mM AuNPs was synthesized. In order to quantify the effect of energy on DEF, irradiation was carried out by Co-60 external radiotherapy and Ir-192 internal radiotherapy. Finally, readings of irradiated and non-irradiated gels were performed by MR imaging. RESULTS: The radiation-induced R2 (1/T2) changes of the gel tubes doped with AuNPs compared to control samples, upon irradiation of beams released by Ir-192 source showed a significant dose enhancement (15.31% ±0.30) relative to the Co-60 external radiotherapy (5.85% ±0.14). CONCLUSION: This preliminary study suggests the feasibility of using AuNPs in radiation therapy (RT), especially in low-energy sources of brachytherapy. In addition, MAGAT polymer gel, as a powerful dosimeter, could be used for 3D visualization of radiation dose distribution of AuNPs in radiotherapy.

Development of a novel lipidic nanoparticle probe using liposomal encapsulated Gd2O3-DEG for molecular MRI.

Recently, it has been showed that gadolinium oxide nanoparticles can provide high-contrast enhancement in magnetic resonance imaging (MRI). Moreover, liposomes due to high biocompatibility have shown unique model systems, with the most successful application being the drug delivery system. As a suitable cell-tracking contrast agent (CA) in molecular MRI (mMRI), the synthesis and optimisation characteristic of a novel paramagnetic liposomes (PMLs) based on gadolinium nanoparticles, essentially composed of a new complex of gadolinium oxide-diethylene glycol (Gd2O3-DEG) loaded in liposomes have been determined in this research. Gd2O3-DEG was prepared by a new supervised polyol method and was encapsulated with liposome by the film hydration method. The paramagnetic liposome nanoparticle (PMLN) sizes ranged from 65 to 170 nm. The r1 of PMLNs and Gd2O3-DEG were much higher than that of Gd-diethylenetriamine penta-acetic acid (Gd-DTPA). In MC/9 cell lines, the experiments showed similar results as in water. PMLNs with lower T1 than Gd-DTPA are sensitive, positive MRI CA that could be attractive candidates for cellular and molecular lipid content targets such as diagnostic applications.

The electrocatalytic examination of cephalosporins at carbon paste electrode modified with CoSalophen.

The electrocatalytic oxidation of cephalexin and cefazolin has been studied at a carbon paste electrode modified with cobalt salophen (CoSal) by cyclic voltammetry. The selectivity of the carbon paste modified with CoSal in detecting cephalexin and cefazolin was examined. To suggest the electrocatalytic mechanism for electro-oxidation of cefazolin, the electrochemical behavior of ceftriaxone was investigated which has a thiol group out of the beta lactam ring. The electrocatalytic oxidation of these antibiotics is shown to be irreversible at the CoSal modified electrode. Scan rate dependence of cefazolin, which is a sulfur-containing compound, has been examined. The results indicated that the electrocatalytic oxidation of the compounds is diffusion controlled. The responses of the modified electrode were compared with those of unmodified electrode and it has shown that the modified electrode has better sensitivity than unmodified electrode to the detection of cefazolin. The overall number of electrons contributed to the oxidation of cefazolin is obtained 1 by chronoamperometry; the number of electron involved in the rate-determining step was 1. The results of differential pulse voltammetry (DPV) using the modified electrode with high sensitivity were applied for the determination of cefazolin in human synthetic serum samples. The linear range was obtained from 1x10(-5) to 1x10(-3)M for DPV determination of cefazolin in buffered solutions (pH 3.0).

Alterations in renal uptake kinetics of the xanthine derivative enprofylline in endotoxaemic mice.

The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.

Effect of a bacterial lipopolysaccharide on biliary excretion of a beta-lactam antibiotic, cefoperazone, in rats.

Klebsiella pneumoniae O3 lipopolysaccharide (LPS) has been found to dramatically modify the pharmacokinetics of the beta-lactam antibiotic cefazolin in rats. This study investigated the effect of LPS on the biliary excretion of the beta-lactam antibiotic cefoperazone (CPZ) in rats. CPZ is known to be actively secreted into the bile by a carrier-mediated transport system. LPS (250 micrograms/kg of body weight) was infused for 20 to 30 min 2 h before an intravenous administration of CPZ (20 mg/kg). The pharmacokinetic parameters of CPZ were estimated by a noncompartment model. LPS induced a significant decrease in the systemic clearance (by approximately 50%) and an increase in the mean residence time of CPZ. Significant decreases were also seen in the bile flow rate and in the biliary recovery of unchanged CPZ in the LPS-treated rats. LPS tended to increase the proportion of urinary excretion of CPZ. LPS significantly decreased the biliary clearance (by approximately 55%) and renal clearance (by approximately 35%) of CPZ. However, no changes in the volume of distribution at steady state for CPZ were observed between the treatment groups. Our findings suggest that LPS induces changes in the pharmacokinetics of CPZ as a result of changes occurring in the biliary secretory system.

Influence of a newly developed quinolone, T-3761, on pharmacokinetics of theophylline in rats.

The effect of a new quinolone, T-3761, on the pharmacokinetics and metabolism of theophylline was investigated with rats. T-3761 at a high dose (20 mg/kg of body weight) was injected intravenously 10 min before an intravenous administration of theophylline (10 mg/kg). The presence of T-3761 slightly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and T-3761 were estimated by noncompartmental methods. A significant decrease (approximately 25%) in the systemic clearance of theophylline was observed in the presence of T-3761. However, no significant changes between the control group and the T-3761-treated groups in the volume of distribution at a steady state were observed. Pretreatment with T-3761 increased the urinary excretion of unchanged theophylline (by approximately 25%) and decreased the nonrenal clearances (by approximately 30%), indicating that T-3761 inhibits the metabolism of theophylline. These findings suggest that T-3761 at the dose used in this study affects the pharmacokinetics and metabolism of theophylline.

Time-dependent changes in the pharmacokinetics and renal excretion of xanthine derivative enprofylline induced by bacterial endotoxin in rats.

Time-dependent changes in the pharmacokinetics and renal handling of enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250 micrograms/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 micrograms/min/kg for inulin and enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for enprofylline and GFR continued over the testing period of 120 min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single injection of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24 h earlier with or without LPS. The pharmacokinetic parameters of enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for enprofylline were observed in rats pretreated 2 and 10 h earlier with LPS, but no such changes were observed in rats pretreated 24 h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of enprofylline, and suggest that LPS at a dose of 250 micrograms/kg, at least, does not induce cytotoxicity to kidney cells.

Brain distribution characteristics of xanthine derivatives and relation to their locomotor activity in mice.

The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg-1, MPX caused a decrease in such activity over 10 mg kg-1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3',5'-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44.6 and 134, > 1000 and 112, 26.4 and 49, and > 1000 and 111 microM for theophylline, enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.

Biliary and renal excretions of cefpiramide in Eisai hyperbilirubinemic rats.

Eisai hyperbilirubinemic mutant rats (EHBRs) with conjugated hyperbilirubinemia were recently derived from Sprague-Dawley rats (SDRs). The pharmacokinetic characteristics of the beta-lactam antibiotic cefpiramide (CPM), which is mainly excreted into bile, were investigated in 10- and 20-week-old EHBRs and were compared with those in 20-week-old healthy SDRs. The pharmacokinetic parameters of CPM after an intravenous administration of 20 mg/kg of body weight were estimated for each rat by noncompartmental methods. When compared with age-matched healthy SDRs, significant decreases (by approximately 30%) in the systemic clearance of CPM were observed in 20-week-old EHBRs. The biliary clearance of CPM in 20-week-old EHBRs markedly decreased to less than 10% of that in age-matched healthy SDRs, while total urinary recovery of unchanged CPM increased to threefold and renal clearance doubled. However, no significant differences in any of the pharmacokinetic parameters of CPM were observed between the two groups of EHBRs. There were no significant differences among the three groups in the steady-state volume of distribution of CPM. The present study indicates that hyperbilirubinemia induces an increase in the urinary excretion ability of CPM in return for a reduction in the biliary excretion.

Influence of endotoxin and lipid A on the renal handling and accumulation of gentamicin in rats.

The contribution of lipid A, an active component of endotoxin (LPS), to changes in the pharmacokinetics, renal handling and intrarenal accumulation of gentamicin induced by Klebsiella pneumoniae LPS was investigated in rats. Either LPS (250 micrograms/kg) or lipid A (equivalent to dose of LPS) was infused 2 h before the administration of gentamicin (10 mg/kg). The effects of LPS and lipid A on the intrarenal accumulation of gentamicin were also evaluated. Significant increases in the levels of plasma creatinine and blood urea nitrogen were observed in both the LPS and lipid A groups. Both LPS and lipid A induced significant decreases in the glomerular filtration rate (by approximately 30%) and systemic clearance of gentamicin (by approximately 25%). No changes in the fraction of urinary excretion (> 0.9) or steady-state volume of distribution of gentamicin were observed between either the control, LPS or lipid A groups. There were no significant differences among the three groups in the tubular reabsorption or intrarenal accumulation of gentamicin. The degree of effect of lipid A on the pharmacokinetics of gentamicin observed in this study was nearly equal to that of LPS. These results suggest that lipid A plays a major role in changes in the pharmacokinetics and renal handling of gentamicin induced by LPS.

On the influence of ionic strength on the equilibrium constant of copper-murexide interaction.

The concentration formation constant for the 1:1 complex between copper(II) and murexide in aqueous solutions has been measured as a function of ionic strength by spectrophotometry at 25 degrees . There is an inverse relationship between the K(c) values and ionic strength. The formation constant at infinite dilution was found to be 6.16 x 10(4). The distance of closest approach for the Cu(2+) ion was estimated as 4.3 +/- 0.3 A.