OBJECTIVE: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. MATERIALS AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (K(trans)) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. RESULTS: P792 group showed a more prominent decrease in K(trans) and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.
Animals ; Antineoplastic Agents/therapeutic use ; Benzophenones/therapeutic use ; Disease Models, Animal ; Heterocyclic Compounds/administration & dosage/*chemistry ; Liver Neoplasms/drug therapy/pathology/*radiography ; *Magnetic Resonance Imaging ; Male ; Organometallic Compounds/administration & dosage/*chemistry ; Rabbits ; Reproducibility of Results ; Valine/analogs & derivatives/therapeutic use

The role of imaging is crucial for the surveillance, diagnosis, staging and treatment monitoring of hepatocellular carcinoma (HCC). Over the past few years, considerable technical advances were made in imaging of HCCs. New imaging technology, however, has introduced new challenges in our clinical practice. In this article, the current status of clinical imaging techniques for HCC is addressed. The diagnostic performance of imaging techniques in the context of recent clinical guidelines is also presented.
Carcinoma, Hepatocellular/*diagnosis/radiography/ultrasonography ; Contrast Media/chemistry ; Ferric Compounds/chemistry ; Humans ; Iron/chemistry ; Liver Neoplasms/*diagnosis/radiography/ultrasonography ; Magnetic Resonance Imaging ; Meglumine/analogs & derivatives/chemistry ; Organometallic Compounds/chemistry ; Oxides/chemistry ; Tomography, X-Ray Computed

In this study, we prepared PLLA/bpV(pic) microspheres, a bpV(pic) controlled release system and examined their ability to protect nerve cells and promote axonal growth. PLLA microspheres were prepared by employing the o/w single emulsification-evaporation technique. Neural stem cells and dorsal root ganglia were divided into 3 groups in terms of the treatment they received: a routine medium group (cultured in DMEM), a PLLA microsphere group (DMEM containing PLLA microspheres alone) and a PLLA/bpV(pic) group [DMEM containing PLLA/bpV(pic) microspheres]. The effects of PLLA/bpV(pic) microspheres were evaluated by the live-dead test and measurement of axonal length. Our results showed that PLLA/bpV(pic) granulation rate was (88.2±5.6)%; particle size was (16.8±3.1)%, drug loading was (4.05±0.3)%; encapsulation efficiency was (48.5±1.8)%. The release time lasted for 30 days. In PLLA/bpV(pic) microsphere group, the cell survival rate was (95.2 ±4.77)%, and the length of dorsal root ganglion (DRG) was 718±95 μm, which were all significantly greater than those in ordinary routine medium group and PLLA microsphere group. This preliminary test results showed the PLLA/bpV(pic) microspheres were successfully prepared and they could promote the survival and growth of neural cells in DRG.
Animals ; Axons ; drug effects ; physiology ; Cells, Cultured ; Delayed-Action Preparations ; chemistry ; pharmacokinetics ; pharmacology ; Drug Compounding ; Female ; Ganglia, Spinal ; drug effects ; metabolism ; physiology ; Immunohistochemistry ; Lactic Acid ; chemistry ; pharmacokinetics ; pharmacology ; Microscopy, Electron ; Microspheres ; Neural Stem Cells ; drug effects ; physiology ; Neurofilament Proteins ; metabolism ; Neurons ; drug effects ; metabolism ; Organometallic Compounds ; chemistry ; pharmacokinetics ; pharmacology ; Polyesters ; Polymers ; chemistry ; pharmacokinetics ; pharmacology ; Pregnancy ; Rats

OBJECTIVETo investigate the effect of lead exposure on copper and copper metalloenzyme and the intervention effect of quercetin.

METHODSTwenty-four specific pathogen-free male Sprague-Dawley rats of good health were randomly divided into control group (n = 8), lead acetate group (n = 8), and lead acetate + quercetin group (n = 8). The rats in lead acetate group were poisoned by drinking water with 1 g/L lead acetate for 8 weeks, while the rats in control group were fed by drinking water with sodium acetate of the same volume for 8 weeks; the rats in lead acetate+quercetin group were intraperitoneally injected with quercetin (30 mg × kg-1 × d-1) for 8 weeks while drinking water with lead acetate. The Morris water maze was used to test the learning and memory abilities of rats. The lead and copper levels in the serum, hippocampus, cortex, and bone were measured by graphite furnace atomic absorption spectrometry. The level of advanced glycation end products, activity of Cu/Zn superoxide dismutase (SOD), and content and activity of ceruloplasmin (CP) in the hippocampus and serum were measured using a test kit. HE staining was performed to observe the pathological changes in the hippocampus.

RESULTSThe Morris water maze test showed that the latency in lead acetate group (52.50±12.04 s) was significantly longer than that in control group (28.08±7.31 s) (P<0.05), and the number of platform crossings was significantly lower in the lead acetate group than in the control group. Compared with those in the control group, the lead levels in the cortex and hippocampus in lead acetate group increased 2.72-fold and 3.79-fold, and the copper in the cortex and hippocampus, and serum free copper levels in lead acetate group increased 1.15-fold, 1.48-fold, and 6.44-fold. Compared with the control group, the lead acetate group had a lower content of CP in the hippocampus (1.23±0.40 U/mg provs0.78±0.08 U/mg pro) and 31.81%and 19.49%decreases in CP content and Cu/Zn SOD activity. Free copper level in serum was positively correlated with the latency and lead levels in the serum, cortex, and hippocampus. The escape latency of rats in lead acetate + quercetin group was decreased by 42.15% (P<0.05). The lead levels in the cortex and hippocampus in lead acetate + quercetin group (0.246 ± 0.58 µg/g and 0.202±0.049 µg/g) were significantly lower than those in lead acetate group (0.391±0.49 µg/g and 0.546±0.120 µg/g), but the free copper and copper levels in the hippocampus and cortex were not significantly reduced. The lead acetate + quercetin group had higher Cu/Zn SOD activity and CP content in the hippocampus than the lead acetate group (P < 0.05). The light microscope observation showed that the number of cells in the hippocampus was reduced with disordered arrangement in the lead acetate group; with quercetin intervention, the hippocampus damage was reduced.

CONCLUSIONLead exposure results in disorder of copper homeostasis, while quercetin may alleviate the damage induced by lead to some extent.

Animals ; Cerebral Cortex ; chemistry ; Copper ; blood ; Hippocampus ; chemistry ; Homeostasis ; Learning ; drug effects ; Male ; Memory ; drug effects ; Organometallic Compounds ; toxicity ; Quercetin ; pharmacology ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism

Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes.
Animals ; Carbon Monoxide ; chemistry ; pharmacokinetics ; toxicity ; Fibroblasts ; drug effects ; Kidney ; drug effects ; Liver ; drug effects ; Mice ; Molecular Structure ; Organometallic Compounds ; chemical synthesis ; chemistry ; pharmacokinetics ; toxicity ; Rats ; Rats, Wistar ; Ruthenium ; chemistry ; pharmacokinetics ; toxicity ; Tissue Distribution

Hepatocyte specific contrast agents including gadoxetic acid and gadobenate dimeglumine are very useful to diagnose various benign and malignant focal hepatic lesions and even helpful to estimate hepatic functional reservoir. The far delayed phase image referred to as the hepatobiliary phase makes the sensitivity of detection for malignant focal hepatic lesions increased, but specificity of malignant diseases, including hepatocellular carcinoma, metastasis and cholangiocarcinoma, characterization remained to be undetermined.
Carcinoma, Hepatocellular/radiography ; Cholangiocarcinoma/radiography ; Contrast Media/chemistry/*diagnostic use ; Hemangioma/radiography ; Humans ; Liver Diseases/*radiography ; Liver Neoplasms/radiography ; Magnetic Resonance Imaging ; Meglumine/*analogs & derivatives/chemistry/diagnostic use ; Organometallic Compounds/chemistry/*diagnostic use

BACKGROUNDThe hairpin cell-penetrating peptides (hCPPs) demonstrate an interesting characteristic of conditioned activation by molecules. We hypothesized that hCPPs have the potential to selectively deliver a paramagnetic gadolinium probe into the matrix metalloproteinase 2 (MMP-2) positive human ovary adenocarcinoma cell lines, SKOV-3.

METHODShCPPs were synthesized and labeled with 1,4,7,10-tetraazacyclododecane-N,N',N'',N''' tetraacetic acid gadolinium (III) (Gd-DOTA) and fluorescein isothiocyanate (FITC) by f-moc strategy using a standard solid phase peptide synthesis protocol. MMP-2 expression and activity were demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR) and zymography. Internalization and location of hCPPs in SKOV-3 cells were observed by fluorescein imaging and flow cytometery. Selective delivery of Gd-DOTA in SKOV-3 cells was observed by magnetic resonance imaging (MRI) and transmission electron microscopy (TEM).

RESULTSThe uptake of hCPPs by SKOV-3 cells depended on the activity of MMP-2. T1WI signals of SKOV-3 cells treated with Gd-DOTA-hCPPs suggested the uptake of Gd-DOTA-hCPPs increased in a time- (r = 0.990, P < 0.01) and concentration-dependent manner (r = 0.964, P < 0.001), but was inhibited by a MMP-2 inhibitor. Electron-dense particles observed in the cytoplasm and nucleus by transmission electron microscopy proved the intracellular penetration of gadolinium.

CONCLUSIONShCPPs can be used as an effective vector for an MRI molecular probe to assess the activity of MMP-2.

Cell Line, Tumor ; Cell-Penetrating Peptides ; adverse effects ; chemical synthesis ; chemistry ; metabolism ; Flow Cytometry ; Heterocyclic Compounds ; adverse effects ; chemical synthesis ; chemistry ; metabolism ; Humans ; Magnetic Resonance Imaging ; Matrix Metalloproteinase 2 ; chemistry ; metabolism ; Microscopy, Electron, Transmission ; Organometallic Compounds ; adverse effects ; chemical synthesis ; chemistry ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

This study is to assess the efficacy of BPCBG on the decorporation of uranium (VI) and protecting human renal proximal tubular epithelial cells (HK-2) against uranium-induced damage. BPCBG at different doses was injected intramuscularly to male SD rats immediately after a single intraperitoneal injection of UO2(CH3COO)2. Twenty-four hours later uranium contents in urine, kidneys and femurs were measured by ICP-MS. After HK-2 cells were exposed to UO2(CH3COO)2 immediately or for 24 h followed by BPCBG treatment at different doses for another 24 or 48 h, the uranium contents in HK-2 cells were measured by ICP-MS, the cell survival was assayed by cell counting kit-8 assay, formation of micronuclei was determined by the cytokinesis-block (CB) micronucleus assay and the production of intracellular reactive oxygen species (ROS) was detected by 2',7'-dichlorofluorescin diacetate (DCFH-DA) oxidation. DTPA-CaNa3 was used as control. It was found that BPCBG at dosages of 60, 120, and 600 micromol kg(-1) resulted in 37%-61% increase in 24 h-urinary uranium excretion, and significantly decreased the amount of uranium retention in kidney and bone to 41%-31% and 86%-42% of uranium-treated group, respectively. After HK-2 cells that had been pre-treated with UO2(CH3COO)2 for 24 h were treated with the chelators for another 24 h, 55%-60% of the intracellular uranium was removed by 10-250 micromol L(-1) of BPCBG. Treatment of uranium-treated HK-2 cells with BPCBG significantly enhanced the cell survival, decreased the formation of micronuclei and inhibited the production of intracellular ROS. Although DTPA-CaNa3 markedly reduced the uranium retention in kidney of rats and HK-2 cells, its efficacy of uranium removal from body was significantly lower than that of BPCBG and it could not protect uranium-induced cell damage. It can be concluded that BPCBG effectively decorporated the uranium from UO2(CH3COO)2-treated rats and HK-2 cells, which was better than DTPA-CaNa3. It could also scavenge the uranium-induced intracellular ROS and protect against the uranium-induced cell damage. BPCBG is worth further investigation.
Animals ; Cell Line ; Cell Survival ; drug effects ; Chelating Agents ; administration & dosage ; chemistry ; pharmacology ; Dose-Response Relationship, Drug ; Epithelial Cells ; cytology ; metabolism ; Humans ; Kidney ; metabolism ; Kidney Tubules, Proximal ; cytology ; Male ; Micronucleus Tests ; Molecular Structure ; Organometallic Compounds ; toxicity ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; metabolism ; Uranium ; metabolism ; urine

Humans ; Organometallic Compounds ; chemistry ; metabolism ; toxicity

Our work focuses on the quality control and structural identification of Photocyanine as a cancer therapeutic photosensitizer. Photocyanine is a mixture which contains four ZnPcS2P2 type substituted Phthalocyanine isomers. In order to obtain the single component from Photocyanine, the mixture of four isomers possessing the similar structures and chemical property had been isolated and purified. An HPLC method with a mixture of methanol-acetonitrile-ion-pair buffer as the mobile phase was applied to isolate the four isomers by means of a semi-preparative C18 column. To remove the salts which were mixed in the preparative product, a SPE C18 column was used to separate the salts by elution with water and then the marker component was eluted by methanol. Subsequently, a column of Sephadex LH-20 gel was applied to elute the crudes with methanol to desalination. The purity of the isolated compound was measured by TLC and four different isomers of phthalocyanine were obtained. The chemical structures of them were elucidated by 1H NMR spectra, gCOSY and NOE1D. An HPLC-DAD method was developed for simultaneously determination of four major isomers in Photocyanine with a C18 column (Grace Smart, 150 mm x 4.6 mm ID, 5 microm). The separation was carried out with a gradient program at a flow rate of 1.0 mL x min(-1). The mobile phase was a mixture of acetonitrile and ion-pair buffer (0.01 mol x L(-1) hexadecyl trimethyl ammonium bromide and 0.01 mol x L(-1) potassium dihydrogen phosphate, adjusted the pH value to 6.8 with potassium hydroxide solution). The resolution values of four isomers were 2.5, 1.20, 1.33, and 1.8. Linear regression analysis for four compounds was performed by the external standard method. Four constituents were linear in the concentration range of 0.005 to 10 microg. The values of relative standard deviation (RSD) of intra-day were 0.12%, 0.66%, 0.99%, and 1.21%, respectively. The limits of detection for four compounds were 15 ng, 20 ng, 12 ng, and 25 ng, respectively. This method was simple, accurate and reproducible. The developed method can be successfully applied to analyze isomers in Photocyanine.
Antineoplastic Agents ; analysis ; chemistry ; Chromatography, High Pressure Liquid ; methods ; Indoles ; analysis ; chemistry ; Isomerism ; Molecular Structure ; Organometallic Compounds ; analysis ; chemistry ; Photochemotherapy ; Photosensitizing Agents ; analysis ; chemistry ; Quality Control