Gd-DTPA Concentration Research Articles

Non-Invasive Imaging Technique for the Estimation of Drug Delivery in Tumors

Non-Invasive Imaging Technique for the Estimation of Drug Delivery in Tumors

Technical Note: Human tissue-equivalent MRI phantom preparation for 3 and 7 Tesla.

While test objects (phantoms) in magnetic resonance imaging (MRI) are crucial for sequence development, protocol validation, and quality control, studies on the preparation of phantoms have been scarce, particularly at fields exceeding 3 Tesla. Here, we present a framework for the preparation of phantoms with well-defined T1 and T2 times at 3 and 7 Tesla. Phantoms with varying concentrations of agarose and Gd-DTPA were prepared and measured at 3 and 7 Tesla using T1 and T2 mapping techniques. An empirical, polynomial model was constructed that best represents the data at both field strengths, enabling the preparation of new phantoms with specified combinations of both T1 and T2 . Instructions for three different tissue types (brain gray matter, brain white matter, and renal cortex) are presented and validated. T1 times in the samples ranged from 698 to 2820ms and from 695 to 2906ms, whereas T2 times ranged from 39 to 227ms and from 34 to 235ms for 3 and 7 Tesla scans, respectively. Models for both relaxation times used six parameters to represent the data with an adjusted R² of 0.998 and 0.997 for T1 and T2 , respectively. Based on the equations derived from the current study, it is now possible to obtain accurate weight specifications for a test object with desired T1 and T2 relaxation times. This will spare researchers the laborious task of trail-and-error approaches in test object preparation attempts.

Appropriate echo time selection for quantitative susceptibility mapping.

The purpose of our study was to clarify the dependence of quantitative susceptibility mapping (QSM) on echo time (TE). We constructed a phantom consisting of six tubes; three tubes were filled with different concentrations (0.5, 1.0, and 2.5mM) of gadopentetate dimeglumine (Gd-DTPA), and three were filled with different concentrations (100, 200, and 350mg/mL) of calcium hydroxyapatite. Real and imaginary images from multi-echo spoiled gradient-echo data (12 echoes) were acquired. We then used four datasets with three serial echoes. The QSM procedure consists of four steps: field map estimation, phase unwrapping, background removal, and dipole inversion. For each sample, we compared the measured mean susceptibility value with the theoretical susceptibility value and conducted a linear regression analysis. Accordingly, the relationship between the measured susceptibility and concentration of Gd-DTPA was shown to agree well with the theoretical values (TEs = 16.4, 20.8, and 25.2ms; slope = 0.24, R2 = 1.00). Furthermore, the relationship between the measured susceptibility and concentration of hydroxyapatite also showed good linearity (TEs = 16.4, 20.8, and 25.2ms; slope = - 0.00121, R2 = 1.00). In conclusion, the optimization of the TE in QSM makes it possible to obtain more detailed information regarding the susceptibility of biomaterials.

Phantom Validation of DCE-MRI Magnitude and Phase-Based Vascular Input Function Measurements.

Accurate, patient-specific measurement of arterial input functions (AIF) may improve model-based analysis of vascular permeability. This study investigated factors affecting AIF measurements from magnetic resonance imaging (MRI) magnitude (AIFMAGN) and phase (AIFPHA) signals, and compared them against computed tomography (CT) (AIFCT), under controlled conditions relevant to clinical protocols using a multimodality flow phantom. The flow phantom was applied at flip angles of 20° and 30°, flow rates (3–7.5 mL/s), and peak bolus concentrations (0.5–10 mM), for in-plane and through-plane flow. Spatial 3D-FLASH signal and variable flip angle T1 profiles were measured to investigate in-flow and radiofrequency-related biases, and magnitude- and phase-derived Gd-DTPA concentrations were compared. MRI AIF performance was tested against AIFCT via Pearson correlation analysis. AIFMAGN was sensitive to imaging orientation, spatial location, flip angle, and flow rate, and it grossly underestimated AIFCT peak concentrations. Conversion to Gd-DTPA concentration using T1 taken at the same orientation and flow rate as the dynamic contrast-enhanced acquisition improved AIFMAGN accuracy; yet, AIFMAGN metrics remained variable and significantly reduced from AIFCT at concentrations above 2.5 mM. AIFPHA performed equivalently within 1 mM to AIFCT across all tested conditions. AIFPHA, but not AIFMAGN, reported equivalent measurements to AIFCT across the range of tested conditions. AIFPHA showed superior robustness.

Evaluation of Maximum and Minimum Signal Intensity and the Linear Relationship between Concentration and Signal Intensity in Saturation Recovery T1-weighted Images by use of a Turbo Fast Low-Angle Shot Sequence.

Background: The relationship between the concentration of contrast agents and signal intensity (SI) are affected by some image parameters, phase-encoding scheme, magnetic field strength, image sequences, and iron oxide nanoparticles used and Gd-DTPA as MRI contrast agents. Objective: In this article, the effect of saturation times (TSs) on the maximum and minimum SI, and also the linear relationship between the concentration of the contrast agent and SI are evaluated. Additionally, we evaluated the concentration of contrast agent that results the minimum SI using a saturation recovery TurboFLASH sequence.Material and Methods: In this experimental study, a phantom was designed to hold vials with different concentrations of Gd-DTPA (0–19.77mmol/L). The mean SI was acquired from the nine central pixels of every vial at various TSs.Results: This study shows that the maximum SI in an image is dependent on short TSs (up to 400ms) and independent of long TSs (400–1000ms). The result also shows that the concentration at which a maximum linear relationship between concentration and SI is maintained that gave an R2 equal to 0.95 and 0.99 dependent on the TS. Moreover, the outcome demonstrates that as TS increases, the concentration of the contrast agent decreases. This causes SI to be minimized.Conclusion: This study demonstrated that the TS is a key parameter for measuring the maximum and minimum SI and also TS plays the role in determining the maximum linear relationship between the MRI contrast agent concentration and SI in an in vivo perfusion study.

Gadopentatic acid affects in vitro proliferation and doxorubicin response in human breast adenocarcinoma cells.

Contrasting agents (CAs) that are administered to patients during magnetic resonance imaging to facilitate tumor identification are generally considered harmless. However, gadolinium (Gd) based contrast agents can be retained in the body, inflicting specific cell line cytotoxicity. We investigate the effect of Gadopentatic acid (Gd-DTPA) on human breast adenocarcinoma MCF-7 cells. These cells exhibit a toggle switch response: exposure to 0.1 and 1mM concentrations of Gd-DTPA enhances proliferation, which is hindered at a higher 10mM concentration. Proliferation is enhanced when cells transition to 3D morphologies in post confluent conditions. The proliferation dependence on the concentration of CA is absent for Hs 578T and MDA-MB-231 triple negative cell lines. MCF-7 cells reveal a double toggle switch related to the expression of VEGF, which goes through high-low-high downregulation when cells are exposed to 0.1, 1, and 10mM Gd-DTPA, respectively. Finally, doxorubicin drug response is assessed, which also reveals a double toggle switch behavior, where drug cytotoxicity exhibits a nonlinear dependence on the CA concentration. A toggle switch in cell characteristics that are exposed to 1mM of Gd-DTPA amplifies the importance of this threshold, affecting several cell behaviors if surpassed. This work emphasizes the important effects that CAs can have on cells, specifically Gd-DTPA on MCF-7 cells, and the implications for cell growth and drug response during clinical and synthetic biology procedures.

Gadolinium-enhanced 7.0 T magnetic resonance imaging assessment of the aqueous inflow in rat eyes in vivo

The goal of this study was to calculate the anterior chamber volume and assess aqueous inflow in rat eyes in vivo, under anesthetic condition. Gadolinium-contrast agent (Gd-DTPA, 234.5 mg/ml) was administered to Sprague−Dawley rat eyes via anterior chamber injection or instillation of 234.5 or 117.25 mg/ml Gd-DTPA in 0.2% azone as eye drops, and changes of Gd signal visualized by 7.0 T magnetic resonance imaging (MRI). The safety of local application of Gd-DTPA and azone were performed after MRI scanning. The anterior chamber injection of Gd-DTPA (234.5 mg/ml) group was used for anterior chamber volume and aqueous inflow calculating. Serial changes in Gd-DTPA relative concentration in the anterior chamber was determined based on the initial Gd signal gray values and the initial relative concentration of Gd-DTPA after anterior chamber Gd-DTPA injection. The mean aqueous inflow in rat eyes in vivo was assessed based on changes in Gd-DTPA relative concentration and the anterior chamber volume. Eye drops of Gd-DTPA (234.5 mg/ml) in 0.2% azone readily allowed safe assessment of the aqueous inflow by 7.0 T MRI. Under anesthetic condition in vivo, the mean anterior chamber volume (ACV) in rats was 8493.6 ± 657.4 μm3, no differences were observed in the aqueous inflow measured by topical instillation of 234.5 mg/ml Gd-DTPA in 0.2% azone (0.182 ± 0.011 μl/min) between that measured by anterior chamber injection (0.165 ± 0.041 μl/min, P > 0.05), Timolol reduced aqueous inflow to 0.124 ± 0.020 μl/min (P < 0.05). Our results indicated that Gd-enhanced 7.0 T MRI allows evaluation of the Gd signal variation and anterior chamber volume in rats in vivo. The aqueous inflow calculation via non-invasive local application of 234.5 mg/ml Gd-DTPA can be assessed by the variability of relative concentration of Gd-DTPA in anterior chamber and ACV in vivo, under anesthetic condition.

In vitro chondrocyte toxicity following long-term, high-dose exposure to Gd-DTPA and a novel cartilage-targeted MR contrast agent.

To determine the concentrations exhibiting toxicity of a cartilage-targeted magnetic resonance imaging contrast agent compared with gadopentetate dimeglumine (Gd-DT-PA) in chondrocyte cultures. A long-term Swarm rat chondrosarcoma chondrocyte-like cell line was exposed for 48h to 1.0-20mM concentrations of diaminobutyl-linked nitroxide (DAB4-DLN) citrate, 1.0-20mM Gd-DTPA, 1.0μM staurosporine (positive control), or left untreated. Cell appearance, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays of metabolic activity, quantitative PicoGreen assays of DNA content, and calcein-AM viability assays were compared. At 1.0-7.5mM, minimal decrease in cell proliferation was found for both agents. At all doses of both agents, cell culture appearances were similar after 24h of treatment. At the higher doses, differences in cell culture appearance were found after 48h of treatment, with dose-dependent declines in chondrocyte populations for both agents. Concentration-dependent declines in DNA content and calcein fluorescence were found after 48h of treatment, but beginning at a lower dose of DAB4-DLN citrate than Gd-DTPA. Dose-dependent decreases in MTT staining (cell metabolism) were apparent for both agents, but larger effects were evident at a lower dose for DAB-DLN citrate. Poor MTT staining of cells exposed for 48h to 20mM DAB4-DLN citrate probably indicates dead or dying cells. The minimal effect of the long-term exposure of model chondrocyte cell cultures to DAB4-DLN citrate and Gd-DTPA concentrations up to 7.5mM (3x typical arthrographic administration) is supporting evidence that these doses are acceptable for MR arthrography. The findings are reassuring given that the experimental exposure to the contrast agents at sustained concentrations was much longer than when used clinically.

Influence of water compartmentation and heterogeneous relaxation on quantitative magnetization transfer imaging in rodent brain tumors.

The goal of this study was to investigate the influence of water compartmentation and heterogeneous relaxation properties on quantitative magnetization transfer (qMT) imaging in tissues, and in particular whether a two-pool model is sufficient to describe qMT data in brain tumors. Computer simulations and in vivo experiments with a series of qMT measurements before and after injection of Gd-DTPA were performed. Both off-resonance pulsed saturation (pulsed) and on-resonance selective inversion recovery (SIR) qMT methods were used, and all data were fit with a two-pool model only. Simulations indicated that a two-pool fitting of four-pool data yielded accurate measures of pool size ratio (PSR) of macromolecular versus free water protons when there were fast transcytolemmal exchange and slow R1 recovery. The fitted in vivo PSR of both pulsed and SIR qMT methods showed no dependence on R1 variations caused by different concentrations of Gd-DTPA during wash-out, whereas the fitted kex (magnetization transfer exchange rate) changed significantly with R1 . A two-pool model provides reproducible estimates of PSR in brain tumors independent of relaxation properties in the presence of relatively fast transcytolemmal exchange, whereas estimates of kex are biased by relaxation variations. In addition, estimates of PSR in brain tumors using the pulsed and SIR qMT methods agree well with one another. Magn Reson Med 76:635-644, 2016. © 2015 Wiley Periodicals, Inc.

P16.33 * AN IN SILICO ESTIMATION OF THE PHARMACOKINETIC PROFILE AND THE DISPOSITION OF GD-DTPA IN BRAIN TUMOR LESIONS OF DIFFERENT VASCULATURE THROUGH PBPK MODELS

Brain tumor lesions (BTL), i.e. high grade gliomas, are known to have a prominence of vasculature, which is promoted through hypoxia mechanisms and differential expression of vascular endothelial growth factor (VEGF). Imaging techniques such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with intra-venous (i.v.) administration of a Gd-based contrast agent (GBCA) are successfully used for the diagnosis and characterization of the BTLs. Tracer kinetics plays an important role in DCE-MRI by assessing the vessel leakage through estimation of the transfer and disposition of GBCAs in a lesion. Physiologically-based pharmacokinetic modeling (PBPK) represents a well-documented approach to estimate in silico the disposition of pharmacologic agents in the body. In this work, we sought to i)present a whole-body PBPK approach in order to estimate the PK profile of Gd-DTPA (Gadopentetic acid, Magnevist®) and ii)evaluate the impact of vascular fraction of tracer's extravascular-extracellular disposition in a simulated BTL. PK profile was assessed through the application of Simcyp® simulator platform and the generation of whole-body PBPK model. BTL was introduced as an additional compartment (∼5% of total brain weight) with tissue characteristics matching those of a brain tumor. In silico clinical trials (ISCTs) were designed by integrating literature data for a virtual population of patients with cancer for Simcyp® and Gd-DTPA properties. The ISCTs were generated for a representative individual and concentrations were estimated for 15 minutes following i.v. bolus injection of Gd-DTPA (0.1 mmol/kg). Given the simulated BTL's size, all parameters were kept constant except for capillary fraction in order to evaluate the impact of vasculature. RESULTS: from the whole-body PBPK simulations estimate the maximum plasma concentration of Gd-DTPA to be 3.0 mM whereas the intracranial blood concentration to be 1.7 mM. Regarding the simulated BTL, concentrations varied between 1.5-1.7 mM for the extravascular-extracellular space following modulation of tissue percentage in capillaries. Finally, zero concentrations are predicted for brain parenchyma and intracellular tissues due to the presence of blood-brain barrier and the absence of cellular intake, transfer or passive mediated, for Gd-DTPA, respectively. The presented in silico approach was capable of assessing the PK profiles of Gd-DTPA and especially its disposition in the extravascular-extracellular space of a putative BTL. The need for exploitation of the imaging techniques with studies correlating image analysis with clinical outcome and in silico tools is of great interest. The incorporation of PBPK models along with in silico tools for tumor growth and/or clinical data could reveal novel approaches for improving DCE-MRI techniques applied in diagnosis and treatment protocols (i.e. novel anti-VEGF treatments).

Effects of the magnetic resonance imaging contrast agent Gd-DTPA on plant growth and root imaging in rice.

Although paramagnetic contrast agents have a wide range of applications in medical studies involving magnetic resonance imaging (MRI), these agents are seldom used to enhance MRI images of plant root systems. To extend the application of MRI contrast agents to plant research and to develop related techniques to study root systems, we examined the applicability of the MRI contrast agent Gd-DTPA to the imaging of rice roots. Specifically, we examined the biological effects of various concentrations of Gd-DTPA on rice growth and MRI images. Analysis of electrical conductivity and plant height demonstrated that 5 mmol Gd-DTPA had little impact on rice in the short-term. The results of signal intensity and spin-lattice relaxation time (T1) analysis suggested that 5 mmol Gd-DTPA was the appropriate concentration for enhancing MRI signals. In addition, examination of the long-term effects of Gd-DTPA on plant height showed that levels of this compound up to 5 mmol had little impact on rice growth and (to some extent) increased the biomass of rice.

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

Coinfused surrogate imaging tracers can provide direct insight into the properties of convection-enhanced delivery (CED) in the nervous system. To better understand the distributive properties of CED in a clinical circumstance, the authors analyzed the imaging findings in pediatric diffuse intrinsic pontine glioma (DIPG) patients undergoing coinfusion of Gd-DTPA and interleukin-13-Pseudomonas exotoxin (IL13-PE). Consecutive patients undergoing CED (maximal rates of 5 or 10 μl/minute) of Gd-DTPA (1 or 5 mM) and IL13-PE (0.125 μg/ml or 0.25 μg/ml) for DIPG were included. Real-time MRI was performed during infusions, and imaging results were analyzed. Four patients (2 males, 2 females; mean age at initial infusion 13.0 ± 5.3 years; range 5-17 years) underwent 5 infusions into DIPGs. Brainstem infusions were clearly identified on T1-weighted MR images at 1-mM (1 infusion) and 5-mM (4 infusions) coinfused Gd-DTPA concentrations. While the volume of distribution (Vd) increased progressively with volume of infusion (Vi) (mean volume 2.5 ± 0.9 ml; range 1.1-3.7 ml), final Vd:Vi ratios were significantly reduced with lower Gd-DTPA concentration (Vd:Vi for 1 mM of 1.6 compared with a mean Vd:Vi ratio for 5 mM of 3.3 ± 1.0) (p = 0.04). Similarly, anatomical distribution patterns were affected by preferential flow along parallel axial fiber tracts, into prior infusion cannula tracts and intraparenchymal air pockets, and leak back around the infusion cannula at the highest rate of infusion. Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. Part of clinical trial no. NCT00880061 ( ClinicalTrials.gov ).

A technique for drug surrogate diffusion coefficient measurement by intravitreal injection

The aim of this work is to develop a technique to accurately measure the diffusion coefficient of drugs and drug surrogates in the vitreous humor using MRI. Fresh bovine eyes were used for drug diffusion study in the vitreous, and Gd-DTPA was chosen as a drug surrogate/contrast agent to visualize the diffusion process by MRI. Experiments were conducted by injecting 30μl of the Gd-DTPA with a concentration of 20mM/l in 0.9% saline in the vitreous of the whole bovine eye. MRI images were acquired at regular intervals for 1.5–2h, and Gd-DTPA concentration was determined from the MRI signal intensity. At each time point, concentration contours were constructed and a least-squares best fit to the corresponding theoretical contours, based on a cylindrical bolus model, was performed. The best fit at different time points resulted in fairly consistent diffusion coefficient values. With the surrogate injection technique perfected, highly-symmetric distribution of Gd-DTPA was observed, allowing for spherically symmetric mathematical models, with adjustments for ellipticity as needed, for the diffusion coefficient analysis. The analysis yielded an average diffusion coefficient value of (3.040±0.274)×10−6cm2/s. The 3-D MRI visualization together with careful symmetric injection of the surrogate/contrast agent has provided a quantitative tool for the accurate measurement of the diffusion coefficient. With symmetric injection and corresponding diffusion theory based on the point-source model with adjustments for nonzero bolus size and asymmetry, strong agreement of theory with experiments has been achieved.

A novel center-of-mass method to measure fluid velocity with MRI

Major obstacles in effective local drug delivery to a target site include non-invasive measurement of the concentration distribution after local administration. Herein, the development of a non-invasive in vitro magnetic resonance imaging (MRI) method is described to quantitatively study the distribution of drug surrogate and to measure fluid flow velocity in the region of interest (ROI). Dynamic contrast enhanced MRI was used to study diffusion–convection transport phenomena of a magnetic resonance contrast agent, Gd-DTPA, in 1% agarose gel. The relationship between the concentration of Gd-DTPA and T1 relaxation time was determined using an inversion recovery MRI technique. The concentration distribution of Gd-DTPA images was estimated from a calibration curve relating T1 relaxation time and the concentration of Gd-DTPA. Using the estimated concentration profiles, center-of-mass points were calculated in a series of time points in order to determine fluid flow velocity, which correlated well with the real volumetric flow velocity at early time points. In this study, we developed a method to analyze MR images quantitatively and to determine fluid flow velocity through a tissue in vivo.

Effect of Echo Time on the Maximum Relationship between Contrast Agent Concentration and Signal Intensity Using FLAIR Sequence

Introduction Contrast-enhanced fluid-attenuated inversion recovery (FLAIR) is one of the MRI sequences that can be used for detection and evaluation of pathological changes in the brain. In this work, we have studied the effect of different echo times (TE) on the maximum relationship between signal intensity and concentration of the contrast agent using the FLAIR sequence. Materials and Methods For assessment of the relationship between signal intensity (SI) and concentration, a water-filled phantom containing vials of different concentrations of Gd-DTPA (0 to 19.77 mmol/L) was used. The mean SI was obtained in the region of interest when T1-weighted images were implemnted. The SI was corrected for coil non-uniformity. Results This study showed that an increase in TE is associated with a decrease in the maximum relationship between SI and concentration. Conclusion TE is an important parameter when the SI is measured in clinical FLAIR studies. The concentration leading to a maximum SI depends on this parameter, with the relevant concentration range decreasing at high TE.

Aerosol Delivery During High Frequency Jet Ventilation: An MRI Evaluation

We have previously demonstrated aerosol delivery during conventional and high frequency oscillatory (HFOV) ventilation using magnetic resonance imaging (MRI) in piglets. There are no reports on aerosol delivery during high frequency jet ventilation (HFJV). To compare delivery of aerosolized gadopentetate dimeglumine (Gd-DTPA) in 3 neonatal ventilator circuits: conventional mechanical ventilation, HFOV, and HFJV. Aerosols of Gd-DTPA (0.025 mol/L) generated using a jet nebulizer placed in the inspiratory limb of each ventilator were delivered into an in vitro lung model simultaneously. Multi-slice T1-weighted spin-echo sequence scans were obtained prior to and after 10 and 20 min of cumulative aerosol delivery. Gd-DTPA concentration was calculated from signal intensity changes, and the total amount of Gd-DTPA was estimated. Gd-DTPA was visualized in the lung model at 10 and 20 min for all 3 ventilators. Gd-DTPA delivery was highest with conventional mechanical ventilation (1.92 μmol at 10 min, 2.89 μmol at 20 min), followed by HFJV (1.59 μmol at 10 min, 1.98 μmol at 20 min) and HFOV (0.79 μmol at 10 min, 1.00 μmol at 20 min). This is the first report of effective aerosol delivery in a neonatal HFJV circuit. Future studies are needed for more accurate quantification of aerosol deposition.

Neuronavigation-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening: A Preliminary Study in Swine

FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure and investigate its feasibility in vivo in large animals. We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 swine by more than 40 sonication procedures and evaluated by MR imaging. Gd-DTPA concentration was quantitated in vivo by MR imaging R1 relaxometry and compared with ICP-OES assay. Brain histology after FUS exposure was investigated using H&E and TUNEL staining. Neuronavigation could successfully guide the focal beam, with precision comparable to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). A FUS pressure of 0.43 MPa resulted in consistent BBB opening. Neuronavigation-guided BBB opening increased Gd-DTPA deposition by up to 1.83 mmol/L (a 140% increase). MR relaxometry demonstrated high correlation with ICP-OES measurements (r(2) = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. Neuronavigation provides sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain can be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

Label-Free Cell Separation Using a Tunable Magnetophoretic Repulsion Force

This paper describes a new label-free cell separation method using a magnetic repulsion force resulting from the magnetic susceptibility difference between cells and a paramagnetic buffer solution in a microchannel. The difference in the magnetic forces acting on different-sized cells is enhanced by adjusting the magnetic susceptibility of the surrounding medium, which depends on the concentration of paramagnetic salts, such as biocompatible gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), dissolved therein. As a proof-of-concept demonstration, Gd-DTPA solutions at concentrations of 0-80 mM were applied to separate U937 cells from red blood cells (RBCs) and to distinguish two different-sized polystyrene (PS) beads (8 and 10 μm in diameter). By increasing the Gd-DTPA concentration from 0 to 40 mM, the separation resolution of PS beads was increased from 0.08 to 0.91. Additionally, we successfully achieved label-free separation of U937 cells from RBCs with >90% purity and 1 × 10(5) cells/h throughput using a 40 mM Gd-DTPA solution.

Abstract 3725: Contrast Enhanced MRI with a Reduced Dose of Gadolinium for Measurement of Blood to Brain Influx Rate in Cerebrovascular Diseases

Dynamic Contrast-Enhanced MRI with a Reduced Dose of Gd-DTPA for Measurement of Blood-to-Brain Influx Rate in Cerebrovascular Diseases In vivo quantification of blood-to-brain transfer rate is of immense importance in diagnosis and monitoring cerebrovascular damages after stroke. Dynamic contrast-enhanced (DCE) methods in CT and MR have been used to collect data about the health of blood-brain barrier (BBB). However high dose of radiation in CT and high dose of contrast agent and long protocol time in MR limit the application of DCE methods in acute stroke imaging. The goal of this study was to investigate DCEMRI with a reduced dose of Gd-DTPA and reduced acquisition time for BBB quantification. Fifteen healthy subjects (23-85 years, 9M, 6F) were randomly divided into 4 groups. Each group received one of 4 different doses of Gd-DTPA (group I, 0.1mmol/Kg, n=4; group II, 0.05 mmol/Kg, n=4; group III, 0.025mmol/Kg, n=4; and group IV, 0.0125 mmol/kg, n=3) for DCEMRI. The MRI data acquisition was performed using a 1.5-Tesla Siemens whole-body scanner with a standard eight-channel array headcoil. Fast T1 sequence, TAPIR, was used to estimate the time-concentration of different doses of Gd-DTPA after IV bolus injection. In addition clinical laboratory data of time-dependent concentration of Gd-DTPA in plasma was obtained from contrast agent manufacturer. Clinical and MR-based data were analyzed for 1) nonlinearity effect of contrast on MR signal and 2) evaluate the percentage of MR sampling error. The reduced dose of Gd-DTPA was used to quantify the BBB transfer rate in 14 MS and 9 cerebral cavernous malformation patients recruited from other studies. Comparison of pharmaco dynamics of Gd-DTPA over a range of different initial doses (less than 0.1 mmol/Kg) shows that 1/4 of the standard dose renders less error in T1 sampling and provides a sufficient dynamics in the intensity of MR signal to achieve a shorter DCEMRI experiment. In comparison to the regular Gd-DTPA-enhanced images, the reduced dose of Gd-DTPA used in DCEMRI is more sensitive in BBB abnormality detection. Comparison of 4 different doses of Gd-DTPA showed that a dose of 25% of 0.1 mmol/Kg, when using a fast T1 mapping protocol, is optimal for BBB permeability quantification in patients. DCEMRI-based BBB influx rate measurements with reduced dose of contrast agent may offer a suitable and less risky biomarker for disease progression and drug trials. Imaging stroke; Left panel represent FLAIR anatomical image of patient with stroke. Right panel represents BBB transfer rate map.

Influence of MRI contrast media on histamine release from mast cells

Mast cells, owing to diversity of secreted mediators, play a crucial role in the regulation of inflammatory response. Together with basophils, mast cells constitute a central pathogenetic element of anaphylactic (IgE-dependent) and anaphylactoid (IgE-independent) reactions. In severe cases, generalized degranulation of mast cells may cause symptoms of anaphylactic shock. The influence of the classical, iodine-based contrast media on mastocyte degranulation has been fully described. Our objective was to determine the influence of the gadolinium-based MRI contrast media on histamine release from mast cells and to compare the activity of ionic and non-ionic preparations of contrast media. To determine the intensity of mast cell degranulation, we used an experimental model based on mastocytes isolated from rat peritoneal fluid. Purified suspensions of mast cells were incubated with various concentrations of Gd-DTPA and Gd-DTPA-BMA, and solutions of PEG 600 which served as a non-toxic osmotic stimulus. The intensity of mast cell activation was presented as mean percentage of histamine released from cells after incubation. The obtained results demonstrate that both ionic and non-ionic preparations of the MRI contrast media are able to induce mast cell degranulation in vitro. It was also proved that the non-ionic MRI contrast media stimulate mast cells markedly more weakly than ionic contrast media at identical concentration. The aforementioned results may suggest a more profitable safety profile of the non-ionic contrast preparations. We may also conclude that triggering of mast cell degranulation after incubation with the solutions of MRI contrast media results from non-specific osmotic stimulation and direct toxicity of free ionic residues.