Diethylenetriaminepentaacetic Acid Bis Research Articles

Liposome-based Nanoprobe With Antibody Conjugation Combined With MRI Contrast Encapsulation as a Potential Diagnostic and Therapeutic Agent for Human Head-and-Neck Cancer Cells

Purpose/Objective(s): To develop a tumor-targeting nanoprobe that selectively binds to epidermal growth factor receptor (EGFR) overexpressing tumor cells by encapsulating a magnetic resonance (MR) imaging contrast agent gadolinium (Gd) and conjugating an EGFR-specific monoclonal antibody within liposome particles. Materials/Methods: Encapsulation of Gd within liposome particles was optimized by combining different concentrations of Dipalmitoylphosphatidylcholine (DPPC), cholesterol, 1,2-dipalmitoyl-sn-glycero-3phosphoethanolamine-N-(biotinyl) (Biotinyl PE), and Diethylenetriaminepentaacetic acid-bis(stearylamide)-Gd (DTPA-BSA-Gd). Avidin was included in the liposomal membrane to conjugate with biotinmodulated anti-EGFR antibody. The resultant probes were characterized for their particle size, surface potential and structural integrity with dynamic light scattering (DLS), Zetasizer, and transmission electronic microscopy (TEM), respectively. In-vitro targeting specificity of the probe was evaluated with fluorescence microscopy by comparing the binding capacity of a fluorescence-labeled probe in a human head and neck cancer cell line, 15B (high EGFR overexpression) and a human embryonic kidney cell line, HEK293 (low EGFR control). The subsequent cytotoxicity toward these two cell lines was quantified by MTT assay. Finally, the in vitro applicability of MRI contrast Gd within the probe was demonstrated by detecting cellbound particles with MR imaging. Results: Using TEM scanning, our probe was observed to be spherical in shape and identical in particle size, approximately 100nm. The surface potential was +5.13mV. The EGFR-specific targeting assay with fluorescence-labeled probes showed significantly high occupancy of the probe on the surface of 15B cells in comparison with HEK293 cells. Furthermore, the T1 relaxation time of this EGFR-specific probe attached to15B cells was measured to be 379.3 ms, shorter than that of control vector without anti-EGFR conjugation (516.2 ms). Conclusion: We have demonstrate targeting specificity of a multi-functional nanoprobe in discriminating high and low EGFR-expressing cells. The incorporation of MRI contrast Gd successfully revealed the cell-targeted probe under MR imaging. These results suggest that this probe can function as a targeting tracer for tumor cells, potentiating it in improving treatment efficacy through MR imaging. Author Disclosure: Y. Kuo: None. C. Hung: None. S.R. Raghavan: None. W.D. D’Souza: None.

Comparative Evaluation of Glutamate-Sensitive Radiopharmaceuticals: Technetium-99m–Glutamic Acid and Technetium-99m–Diethylenetriaminepentaacetic Acid–bis(Glutamate) Conjugate for Tumor Imaging

Single-photon emission computed tomography has become a significant imaging modality with huge potential to visualize and provide information of anatomic dysfunctions that are predictive of future diseases. This imaging tool is complimented by radiopharmaceuticals/radiosubstrates that help in imaging specific physiological aspects of the human body. The present study was undertaken to explore the utility of technetium-99m (⁹⁹(m)Tc)-labeled glutamate conjugates for tumor scintigraphy. As part of our efforts to further utilize the application of chelating agents, glutamic acid was conjugated with a multidentate ligand, diethylenetriaminepentaacetic acid (DTPA). The DTPA-glutamate conjugate [DTPA-bis(Glu)] was well characterized by IR, NMR, and mass spectroscopy. The biological activity of glutamic acid was compared with its DTPA conjugate by radiocomplexation with ⁹⁹(m)Tc (labeling efficiency ≥98%). In vivo studies of both the radiolabeled complexes ⁹⁹(m)Tc-Glu and ⁹⁹(m)Tc-DTPA-bis(Glu) were then carried out, followed by gamma scintigraphy in New Zealand albino rabbits. Improved serum stability of ⁹⁹(m)Tc-labeled DTPA conjugate indicated that ⁹⁹(m)Tc remained bound to the conjugate up to 24 hours. Blood clearance showed a relatively slow washout of the DTPA conjugate when compared with the labeled glutamate. Biodistribution characteristics of the conjugate in Balb/c mice revealed that DTPA conjugation of glutamic acid favors less accumulation in the liver and bone and rapid renal clearance. Tumor scintigraphy in mice showed increasing tumor accumulation, stable up to 4 hours. These preliminary studies show that ⁹⁹(m)Tc-DTPA-bis(Glu) can be a useful radiopharmaceutical for diagnostic applications in single-photon emission computed tomography imaging.

Heat-activated Liposomal MR Contrast Agent: Initial in Vivo Results in Rabbit Liver and Kidney

To evaluate by using in vivo magnetic resonance (MR) imaging the functionality of a liposomal paramagnetic contrast agent with T1 relaxivity that rapidly and markedly increases at temperatures above the gel-to-liquid crystalline phase transition temperature (T(c)) of the liposome membrane. Liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) was injected intravenously at a dose of 0.4 or 1.2 mL (containing 10 or 30 micromol of gadolinium, respectively) per kilogram of body weight shortly before the application of focused ultrasound in liver (seven rabbits) or kidney (three rabbits). VX2 tumors had been implanted in liver in four of the rabbits. Eighteen locations in liver (13 in normal tissue, five in tumor) and 12 locations in kidney were sonicated. MR thermometry was performed during sonications. Signal intensity enhancement was evaluated on T1-weighted images acquired after the tissue cooled, and enhanced zones were compared with isotherms at T(c) of the liposome membrane (approximately 57 degrees C) by using Bland-Altman analysis. In liver, enhanced zones also were compared with areas of histologically verified thermal damage. The threshold temperature of enhancement at T1-weighted imaging was verified by monitoring the signal intensity increase after 10 sonications at varied powers in two locations in normal liver tissue. Persistent enhancement was observed on T1-weighted images at all sonicated liver locations. In liver, enhanced zones on T1-weighted images were contiguous both with 57 degrees C isotherms (25 measurements; mean difference +/- SD, 0.4 mm +/- 1.2) and with histologically verified areas of necrosis (seven measurements; mean difference +/- SD, 0.1 mm +/- 0.9). The threshold temperature of enhancement at T1-weighted imaging in normal liver was 53 degrees -57 degrees C. In kidney, enhanced zones on T1-weighted images did not match the isotherms. The liposomal contrast agent was effective at in vivo MR thermometry in liver but not in kidney.

Hydrates of Gadolinium Diethylenetriaminepentaacetic Acid Bis(methylamide) as Studied by X-ray Diffraction

The crystal structures of two hydrates of the title compound (gadodiamide I and III) have been determined by single-crystal X-ray diffraction. Gadodiamide I crystallises in the non-centrosymmetric ...

Thermosensitive paramagnetic liposomes for temperature control during MR imaging-guided hyperthermia: In vitro feasibility studies

Magnetic resonance (MR) imaging-based temperature monitoring has gained interest for use in general hyperthermia treatment of tumors. Such therapy requires an accurate control of the temperature, which should range from 41 degrees to 45 degrees C. A novel type of thermosensitive MR agent is proposed: liposome-encapsulated gadolinium chelates whose temperature response is linked to the phase-transition properties of the liposome carrier. In vitro relaxometry and MR imaging were used to evaluate the thermosensitivity of the contrast properties of liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) (Gd-DTPA-BMA). T1 relaxivity (rl) measurements of liposomal Gd-DTPA-BMA were undertaken at 0.47 T and at temperatures of 20 degrees-48 degrees C. MR imaging was performed at 2.0 T with a gel phantom containing inserts of liposomes. Diffusion-weighted and T1-weighted gradient-recalled echo images were acquired as the phantom was heated from 22 degrees to about 65 degrees C. At ambient temperature, the r1 of liposomal Gd-DTPA-BMA was exchange limited due to slow water exchange between the liposome interior and exterior. A sharp, marked increase in r1 occurred as the temperature reached and exceeded the gel-to-liquid crystalline phase-transition temperature (Tm) of the liposomes (42 degrees C). The relaxation enhancement was mainly attributable to the marked increase in transmembrane water permeability, yielding fast exchange conditions. There was good correlation between the relaxometric and imaging results; the signal intensity on T1-weighted gradient-recalled echo images increased markedly as the temperature approached Tm. The temperature sensitivity of the diffusion-weighted technique differed from that of the liposome-based T1-weighted approach, with an apparent water diffusion coefficient increasing linearly with temperature. Since the transition from low to high signal intensity occurred in the temperature range of 38 degrees - 42 degrees C, the investigated paramagnetic liposomes have a potential role as "off-on" switches for temperature control during hyperthermia treatment.

Synthesis of water soluble DTPA complexes with pendant uracil moieties capable of forming complementary hydrogen bonds

Two new DTPA (diethylenetriaminepentaacetic acid) functionalised bis(amides) with pendant uracil moieties have been synthesised from the condensation reaction between DTPA bis(anhydride) and 5-aminouracil or 5,6-diaminouracil. These ligands are representative of an increasing number of ligands capable of forming triple hydrogen bonds with complementary organic bases. However, these ligands are unusual since they form water soluble complexes with a variety of metal ions. In this paper, the syntheses of the two DTPA-uracil ligands, seven metal complexes and the crystal structure of the bismuth complex of DTPA bis(4,5-diamino-6-hydroxy-2-mercaptopyrimidine) L1 are reported. The most important feature of this solid state structure is that the two arms on which the uracil moieties are situated have a high degree of rotational freedom and this allows these groups to form multiple hydrogen bonds involving both uracil moieties on one side of the molecule.

Gadodiamide injection at two dose levels in MRI of CNS lesions: a phase-III study

A double-blind, randomized, parallel study was conducted to evaluate the safety and diagnostic utility of gadodiamide injection (a nonionic chelate of gadolinium and diethylenetriamine pentaacetic acid bis-(methylamide) [Gd-DTPA-BMA]) when administered IV for MRI of the central nervous system (CNS) at doses of 0.1 mmol/kg body weight (b. w.) or 0.3 mmol/kg b. w. A total of 24 patients received the lower dose and 23 the higher dose. Gadodiamide injection was administered to patients referred for MRI due to known or suspected CNS lesions. No clinically significant difference in blood parameters or efficacy was found between the two groups. The number of patients with adverse events other than discomfort was higher in the 0.3 group compared with the 0.1 group. In the 0.1 group, none of the 24 patients experienced any adverse events other than discomfort, and in the 0.3 group, 5 of 23 patients (21.7%) experienced a total of five adverse events other than discomfort. All adverse events were of mild or moderate intensity. Postinjection MR scans provided new information that affected patient management in the case of 6 patients in the 0.1 group and 9 in the 0.3 group.

Determination of elevated levels of dysprosium in serum by electrothermal atomic absorption spectrometry

A method has been developed for the determination of elevated levels of dysprosium in serum, from human beings or animals exposed to a dysprosium magnetic resonance imaging (MRI) contrast agent, by electrothermal atomic absorption spectrometry. Several potential chemical modifiers were tested in order to increase the sensitivity and to overcome the memory effect normally experienced with dysprosium. The following elements were tested as potential modifiers: lanthanum, europium, gadolinium, holmium, thulium, ytterbium, lutetium, thorium, tungsten, rhodium and palladium. Among these, lanthanum and gadolinium gave the most obvious positive effects on the analytical performance. By adding 5 µg lanthanum or 10 µg gadolinium to the tube, after the introduction of the sample, increased sensitivity, lowered limit of detection, reduced memory effect and improved precision of the method were obtained. Gadolinium was chosen as the most suitable modifier of the two. The analytical performance of the method was validated by adding dysprosium, as the MRI contrast agent dysprosium diethylenetriaminepentaacetic acid bis(methylamide)(DyDTPA-BMA), to the serum reference material Seronorm. The accuracy for the concentration range 10–400 ng ml–1 dysprosium was between 95 and 104%(recovery), the repeatability was typically < 2.6% RSD, the reproducibility was between 2.3 and 5.8% RSD and the limit of detection (3s) was 1.1 ng ml–1 of Dy (absolute mass 11 pg) in Seronorm. The characteristic mass based on area measurements was 18 pg. The memory effect of the final method was < 6%, measured as the % carryover of the previous atomization signal when a blank was atomized. The effect of adding CHF3(Freon 23) to the purge gas was also investigated.

Perfusion and diffusion MR imaging of thromboembolic stroke.

A carotid embolic stroke model in rats was studied with a combination of diffusion- and perfusion-sensitive magnetic resonance (MR) imaging at 4.7 T. Capillary blood deoxygenation changes were monitored during formation of focal ischemia by acquiring multisection magnetic susceptibility-weighted echo-planar images. A signal intensity decrease of 7% +/- 3 in ischemic brain (1% +/- 2 in normal brain) was attributable to a T2* decrease due to increased blood deoxygenation, which correlated well with subsequently measured decreases in the apparent diffusion coefficient. The same multisection methods were used to track the first-pass transit of a bolus of dysprosium-DTPA-BMA [diethylenetriaminepentaacetic acid-bis(methylamide)] to assess relative tissue perfusion before and after stroke and after treatment with a thrombolytic agent. Analysis of contrast agent transit profiles suggested a total perfusion deficit in ischemic tissue and essentially unchanged perfusion in normal brain tissue after stroke.

First pass of an MR susceptibility contrast agent through normal and ischemic heart: gradient-recalled echo-planar imaging.

Gradient-recalled echo-planar magnetic resonance (MR) imaging was used to monitor the first pass of a magnetic susceptibility contrast agent through the heart of normal rats and rats subjected to 60-minute occlusion of the anterior branch of the left main coronary artery. Each animal (six normal and six ischemic) received four doses (0.05, 0.1, 0.15, and 0.2 mmol/kg) of Dy-DTPA-BMA [diethylenetriaminepentaacetic acid-bis(methylamide)] administered as a bolus volume of 1.0 mL/kg. In both normal and ischemic rats, signal intensity in nonischemic myocardium was reduced by the contrast agent in a dose-dependent manner. Signal intensity in the ischemic zone was reduced much less, so that at a contrast agent dose of 0.1 mmol/kg or greater the ischemic zone was clearly defined as a high-intensity zone on echo-planar images. Plots of the change in the apparent T2* relaxation rate (delta R2*) during the peak bolus effect versus injected dose were well fit by straight lines for normal, nonischemic, and ischemic myocardium but not for blood in the left ventricle. No difference was seen between myocardial response in normal animals and in nonischemic regions in animals with coronary artery occlusion. These findings suggest that the contrast agent-induced changes in tissue T2* are monoexponential and support the idea that data derived from contrast transit studies may be useful for calculation of myocardial blood flow.

Thermodynamics, proton NMR, and fluorescence studies for the complexation of trivalent lanthanides, calcium(2+), copper(2+), and zinc(2+) by diethylenetriaminepentaacetic acid bis(methylamide)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThermodynamics, proton NMR, and fluorescence studies for the complexation of trivalent lanthanides, calcium(2+), copper(2+), and zinc(2+) by diethylenetriaminepentaacetic acid bis(methylamide)Emil N. Rizkalla, Gregory R. Choppin, and William CacherisCite this: Inorg. Chem. 1993, 32, 5, 582–586Publication Date (Print):March 1, 1993Publication History Published online1 May 2002Published inissue 1 March 1993https://doi.org/10.1021/ic00057a016RIGHTS & PERMISSIONSArticle Views150Altmetric-Citations38LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (480 KB) Get e-Alerts Get e-Alerts

Determination of dysprosium in monkey serum by inductively-coupled plasma atomic emission spectrometry (ICP-AES) after the administration of Sprodiamide Injection, a new contrast medium for magnetic resonance imaging

Sprodiamide Injection (S-043 Injection, Nycomed Salutar; WIN 59080, Sterling Winthrop) is a magnetic susceptibility-based MRI contrast agent which contains 500 mM dysprosium diethylenetriaminepentaacetic acid bis(methylamide) (DyDTPA-BMA), and 25 mM caldiamide sodium (CaNaDTPA-BMA). A study was conducted to evaluate clearance of drug in cynomolgus monkeys. Eighteen cynomolgus monkeys, divided into three groups of six animals each, were administered Sprodiamide Injection intravenously at dose levels of 0.25, 0.5 and 2.5 mmol kg −1 respectively. The concentration of dysprosium in serum was determined in a monkey serum—hydrochloric acid matrix by inductively-coupled plasma atomic emission spectrometry (ICP-AES). The ICP-AES method was demonstrated to be valid for sensitivity, precision, accuracy and specificity. The dynamic range was linear from 0 to 50 μg ml −1 and the limit of quantification was 24 ng ml −1. The measured dysprosium concentration in monkey serum ranged from 0 to 339 μg ml −1 for the 0.25 mmol kg −1 Sprodiamide Injection dose group, from 0 to 633 μg ml −1 for the 0.5 mmol kg −1 and from 0 to 2920 μg ml −1 for 2.5 mmol kg −1 dose groups. Dysprosium was not detected after 480 min in any of the serum samples from the 0.25 and 0.5 mmol kg −1 dose groups after the administration of Sprodiamide Injection. All the monkeys in the 2.5 mmol kg −1 dose group, with one exception, required 720 min for clearance of the drug from the serum. The drug was completely cleared from serum in all monkeys within 24 h.

Effect of Gd-DTPA-BMA on magnetization transfer: application to rapid imaging of cardiac ischemia.

The addition of a paramagnetic contrast agent reduces the magnetization transfer effect between the free and restricted proton pools in both agar phantoms and cardiac muscle tissue. This reduction is due to the reduction in the intrinsic T1 of the free proton pool and increases the signal observed after a given magnetization transfer sequence. Images of ex vivo piglet hearts were obtained with a segmented snapshot FLASH (fast low-angle shot) sequence with a 128 x 128 matrix, four segments, and two signals averaged, resulting in an imaging time of 7 seconds. Magnetization transfer was induced by applying a DANTE (delays alternating with nutations for tailored excitations) pulse sequence in the intersegment interval. This was an efficient method of inducing magnetization transfer because it excites the restricted proton pool across the full frequency spectrum. Ischemia due to occlusion of the left anterior descending branch of the coronary artery could be visualized after infusion of gadolinium diethylenetriaminepentaacetic acid-bis(methylamide) (DTPA-BMA). Although the ischemia could be seen with the basic sequence, the contrast between ischemic and non-ischemic tissue improved when the magnetization transfer sequence was included. The most marked improvements in magnetization transfer were achieved with low doses of Gd-DTPA-BMA.

Preliminary clinical trial of gadodiamide injection: A new nonionic gadolinium contrast agent for MR imaging

The safety and efficacy of a newly developed intravenous formulation of the nonionic contrast agent gadolinium diethylenetriaminepentaacetic acid-bis(methylamide), formulated as gadodiamide injection, was investigated. In 30 patients who underwent spin-echo magnetic resonance (MR) imaging before and after contrast agent enhancement, the enhanced images had characteristics judged similar to those of images enhanced by means of available gadolinium compounds. In 15 patients, contrast agent administration was of major diagnostic help, either revealing lesions not apparent without enhancement or providing important lesion characterization. In 12 patients, the lack of abnormal enhancement patterns was important in excluding the presence of disease. In three patients, the contrast agent did not provide information additional to that obtained with the unenhanced T1- and T2-weighted images. No clinically significant changes were observed in vital signs, neurologic status, or laboratory results. The authors conclude that, in this limited series, gadodiamide injection proved to be a safe and useful MR imaging contrast agent for evaluation of the central nervous system and surrounding structures.

Demarcation of myocardial ischemia: magnetic susceptibility effect of contrast medium in MR imaging.

Dysprosium diethylenetriamine-pentaacetic acid-bis (methylamide) (DTPA-BMA), a new nonionic contrast medium for magnetic resonance (MR) imaging, produces signal loss on T2-weighted images because of induced magnetic field gradients. The potential of this agent to delineate myocardial ischemia was investigated in 10 rats with acute (30 minutes) occlusion of the left coronary artery. T2-weighted MR images were acquired before and for 1 hour after intravenous administration of 1 mmol/kg of Dy-DTPA-BMA. Before administration of the contrast medium, signal intensity (SI) in the ischemic region was significantly greater than that in the normal myocardium; however, the borders of the ischemic region were not consistently distinct. The contrast medium caused marked decrease in SI of normal myocardium (18% +/- 3% of the control value), only slight decrease in the jeopardized region (76% +/- 6% of the control value), and no discernible effects on heart rate or blood pressure. Substantial contrast between normal and ischemic myocardium persisted for 1 hour. Moderate signal loss was observed in skeletal muscle. Dy-DTPA-BMA has the potential to demarcate the myocardial area in jeopardy as a region of high signal intensity because it erases signal preferentially in the normal myocardium.