Gadolinium-diethylenetriamine Pentaacetic Acid Research Articles

Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.

Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function. To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs). Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and 3H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison. MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of 3H-muscimol (Vd; R=0.94). Mean Vd of infused animals was 37.9 mm3±11.7 mm3 and mean Vd: Vi 7.6±2.3. Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.

Stimulation Modeling on Three-Dimensional Anisotropic Diffusion of MRI Tracer in the Brain Interstitial Space.

Purpose: To build a mathematical model based magnetic resonance (MR) method to simulate drug anisotropic distribution in vivo in the interstitial space (ISS) of the brain.Materials and Methods: An injection of signal intensity-related gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), which is an exogenous drug, was administered, and its diffusion was traced in the ISS of the brain using MRI. Dynamic MRI scans were performed to monitor and record the changes in signal intensity in each pixel of the region of interest. The transport parameters were calculated using the modified equation to simulate three-dimensional anisotropic diffusion, which was resolved using a Laplace transform and a linear regressive model.Results: After Gd-DTPA was introduced into the caudate nucleus, its distribution was demonstrated in real time. As the Gd-DTPA gradually cleared, the associated hyperintensity attenuated over time. The average diffusion coefficient (D) and the clearance rate constant (k) were (1.305 ± 0.364) × 10−4 mm2/s and (1.40 ± 0.206) × 10−5 s−1, respectively.Discussion: The combination of trace-based MRI and modified diffusion mathematical models can visualize and measure the three-dimensional anisotropic distribution of drugs in the ISS of the brain.

Rapid Magnetic 3D Printing of Cellular Structures with MCF-7 Cell Inks

A contactless label-free method using a diamagnetophoretic ink to rapidly print three-dimensional (3D) scaffold-free multicellular structures is described. The inks consist of MCF-7 cells that are suspended in a culture medium to which a paramagnetic salt, diethylenetriaminepentaacetic acid gadolinium (III) dihydrogen salt hydrate (Gd-DTPA), is added. When a magnetic field is applied, the host fluid containing the paramagnetic salt is attracted towards regions of high magnetic field gradient, displacing the ink towards regions with a low gradient. Using this method, 3D structures are printed on ultra-low attachment (ULA) surfaces. On a tissue culture treated (TCT) surface, a 3D printed spheroid coexists with a two-dimensional (2D) cell monolayer, where the composite is termed as a 2.5D structure. The 3D structures can be magnetically printed within 6 hours in a medium containing 25 mM Gd-DTPA. The influence of the paramagnetic salt on MCF-7 cell viability, cell morphology, and ability of cells to adhere to each other to stabilize the printed structures on both ULA and TCT surfaces is investigated. Gene expressions of hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) allow comparison of the relative stresses for the printed 3D and 2.5D cell geometries with those for 3D spheroids formed without magnetic assistance. This magnetic printing method can be potentially scaled to a higher throughput to rapidly print cells into 3D heterogeneous cell structures with variable geometries with repeatable dimensions for applications such as tissue engineering and tumour formation for drug discovery.

The use of a binary chelate formulation: Could gadolinium based linear contrast agents be rescued by the addition of zinc selective chelates?

Tissue and bone retention of gadolinium based contrast agents (GBCAs) has become a clinical concern because of the potential short and long term toxic effects of free gadolinium. This is a critical problem for most open-chain agents that more readily transmetallate in vivo, in comparison to macrocyclic compounds. Gadolinium diethylene tri-aminepentaacetic acid bis-glucosamide (Gd-DTPA-BIGA) is an experimental, open-chain contrast agent which has a significantly increased relaxivity coefficient in comparison to other GBCAs. This results in greater signal intensity and improved contrast enhancement. These superior imaging qualities initiated a search for a solution to the transmetallation of this agent. Plasma zinc is a well-known GBCA transmettalation agent. Since the base chelate of Gadodiamide (Gd-DPTA-Bis-Methylamide or Omniscan), DTPA-Bis-Methylamide (DTPA-BMA), readily transmettalates with and binds serum zinc, we hypothesized that a plasma “zinc sink,” may significantly reduce transmetallation of linear agents. 5% DTPA-BMA was added to a formulation of Gd-DTPA-BIGA, which was tested against the original formulation of Gd-DTPA-BIGA with 0.2% of the base chelate DTPA-BIGA. These formulations, including gadodiamide, were labeled with 153GdCl3 followed by infusion into cohorts of Sprague Dawley rats which were sacrificed at 1, 30 and 60 days. Internal organs were harvested, along with blood, skin and femur, and analyzed for residual gadolinium. A subset of tissues were also interrogated with ICP-MS. Labeled Gadodiamide and saline where used as controls.Conclusion: The addition of 5% DTPA-BMA, as a zinc binding agent, reduced the transmetallation of the linear agent Gd-DTPA-BIGA, in comparison to its original formulation supplemented with 0.2% BIGA. This result indicates that supplementing linear GBCAs with ancillary chelates may hold promise for reducing, or eliminating the biological archiving of gadolinium in tissues. In addition, this paper provides valuable animal data on the long term retention of gadolinium from linear based contrast agents.

Size-selective filtration of the atrial wall estimated from the accumulation of tracers in the kidney of the mussel Mytilus galloprovincialis.

In order to determine the molecular weight cut-off (MWCO) for the atrial wall filtration into kidneys of the Mytilus galloprovincialis, we employed five magnetic resonance (MR) tracers: manganese chloride (Mn2+), gadolinium chloride (Gd3+), manganese-ethylenediaminetetraacetic acid (MnEDTA), gadolinium-diethylenetriamine pentaacetic acid (GdDTPA) and oligomer-based contrast agent (CH3-DTPA-Gd). After injection of the MR tracers (1 or 2 mmol l-1×0.1ml) into the visceral mass, T1-weighted MR imaging (T1w-MRI) and the longitudinal relaxation rates (1/T1=R1) were measured at 20°C. The MR tracers were distributed uniformly in the visceral mass within 1 h after injection. The T1w-MRI intensity and R1 of the kidney (R1K) were increased by Mn2+ and MnEDTA, with urine concentrations estimated at 210 and 65 µmoll-1, respectively. The rest of the tracers showed only minimal or no increase. When the mussels were additionally incubated in seawater with 10 µmoll-1 MnCl2, R1K was increased in the GdDTPA group, but not in the GdCl3 group. Therefore, Gd3+ might have inhibited renal accumulation of Mn2+ and Gd3+ Incubation in seawater with 10 µmoll-1 MnEDTA showed no increase in the R1K, but additional incubation with 10 µmoll-1 MnCl2 caused an increase in R1K It is suggested that injected MnEDTA was filtrated as MnEDTA per se, and not likely separated into free Mn2+ Thus, we concluded that the MWCO of the atrial wall of the M. galloprovincialis is around 0.5 kDa, which is almost 1/100 of that for vertebrate animals, and suggests a reduction in efforts to reabsorb metabolites and osmolytes from the urine.

Magnetic Heating Stimulated Cargo Release with Dose Control using Multifunctional MR and Thermosensitive Liposome.

Rationale: Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. In this setting, real-time monitoring of therapy and tumor site would give the clinicians a handle to observe therapeutic response and to quantify drug amount to optimize the treatment. In this work, we developed a liposome-based cargo (cancer drugs) delivery strategy that could simultaneously monitor the real-time alternating magnetic field-induced cargo release from the change in MRI relaxation parameter R1 and the location and condition of liposome from the change in R2. The tumor site can then be monitored during the cargo release because liposomes would passively target the tumor site through the enhanced permeability and retention (EPR) effect. Physical insights from the experimental results and corresponding Monte Carlo spin dynamics simulations were also discussed.Methods: Superparamagnetic iron oxide (SPIO) nanoparticles, diethylenetriaminepentaacetic acid gadolinium(III) (Gd(III)-DTPA), and a model cancer drug (fluorescein) were co-loaded in PEGylated thermosensitive liposomes. The liposomes were characterized by transmission electron cryo-microscopy (cryoTEM), dynamic light scattering (DLS), and inductively coupled plasma optical emission spectrometry (ICP-OES). Alternating magnetic field (AMF) was used to create controlled mild hyperthermia (39-42°C) and facilitate controlled cargo (fluorescein) release from the thermosensitive liposomes. MRI relaxation parameters, R1 and R2, were measured at room temperature. The temporal variation in R1 was used to obtain the temporal profile of cargo release. Due to their similar sizes, both the gadolinium and cargo (model cancer drug fluorescein) would come out of the liposomes together as a result of heating. The temporal variation in R2 was used to monitor SPIO nanoparticles to enhance the tumor contrast. Monte Carlo spin dynamics simulations were performed by solving the Bloch equations and modeling SPIO nanoparticles as magnetized impenetrable spheres.Results: TEM images and DLS measurements showed the diameter of the liposome nanoparticle ~ 200 nm. AMF heating showed effective release of the model drug. It was found that R1 increased linearly by about 70% and then saturated as the cargo release process was completed, while R2 remained approximately constant with an initial 7%-drop and then recovered. The linear increase in R1 is consistent with the expected linear cargo release with time upon AMF heating. Monte Carlo spin dynamics simulations suggest that the initial temporal fluctuation of R2 is due to the plausible changes of SPIO aggregation and the slow non-recoverable degradation of liposomal membrane that increases water permeability with time by the heating process. The simulations show an order of magnitude increase in R2 at higher water permeability.Conclusion: We have performed MR parameter study of the release of a cargo (model cancer drug, fluorescein) by magnetic heating from thermosensitive multifunctional liposomes loaded with dual contrast agents. The size of the liposome nanoparticles loaded with model cancer drug (fluorescein), gadolinium chelate, and SPIO nanoparticles was appropriate for a variety of cancer therapies. A careful and detailed analysis with theoretical explanation and simulation was carried out to investigate the correlation between MRI relaxation parameters, R1 and R2, and different cargo release fractions. We have quantified the cargo release using R1, which shows a linear relation between each other. This result provides a strong basis for the dosage control of drug delivered. On the other hand, the fairly stable R2 with almost constant value suggests that it could be used to monitor the position and condition of the liposomal site, as SPIO nanoparticles mostly remained in the aqueous core of the liposome. Because our synthesized SPIO-encapsulated liposomes could be targeted to tumor site passively by the EPR effect, or actively through magnetofection, this study provides a solid ground for developing MR cancer theranostics in combination of this nanostructure and AMF heating strategy. Furthermore, our simulation results predict a sharp increase in R2 during the AMF heating, which opens up the exciting possibility of high-resolution, high-contrast real-time imaging of the liposomal site during the drug release process, provided AMF heating could be incorporated into an MRI setup. Our use of the clinically approved materials, along with confirmation by theoretical simulations, make this technique a promising candidate for translational MR cancer theranostics.

Rapid Magnetic 3D Printing of Cellular Structures with MCF-7 Cell Inks.

A contactless label-free method using a diamagnetophoretic ink to rapidly print three-dimensional (3D) scaffold-free multicellular structures is described. The inks consist of MCF-7 cells that are suspended in a culture medium to which a paramagnetic salt, diethylenetriaminepentaacetic acid gadolinium (III) dihydrogen salt hydrate (Gd-DTPA), is added. When a magnetic field is applied, the host fluid containing the paramagnetic salt is attracted towards regions of high magnetic field gradient, displacing the ink towards regions with a low gradient. Using this method, 3D structures are printed on ultra-low attachment (ULA) surfaces. On a tissue culture treated (TCT) surface, a 3D printed spheroid coexists with a two-dimensional (2D) cell monolayer, where the composite is termed as a 2.5D structure. The 3D structures can be magnetically printed within 6 hours in a medium containing 25 mM Gd-DTPA. The influence of the paramagnetic salt on MCF-7 cell viability, cell morphology, and ability of cells to adhere to each other to stabilize the printed structures on both ULA and TCT surfaces is investigated. Gene expressions of hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) allow comparison of the relative stresses for the printed 3D and 2.5D cell geometries with those for 3D spheroids formed without magnetic assistance. This magnetic printing method can be potentially scaled to a higher throughput to rapidly print cells into 3D heterogeneous cell structures with variable geometries with repeatable dimensions for applications such as tissue engineering and tumour formation for drug discovery.

Measurement of the magnetic susceptibility of subtle paramagnetic solutions using the diamagnetic repulsion of polymer microparticles.

Herein, we described a microfluidic device that enabled the measurement of magnetic susceptibility of a subtle paramagnetic solution that could not be determined by conventional magnetic susceptibility measurement methods such as a superconducting quantum interference device (SQUID). We measured the diamagnetic repelling velocity of polystyrene microparticles suspended in a weak paramagnetic solution including 50-150 mM of gadolinium-diethylenetriamine penta-acetic acid (GD-DTPA) and superparamagnetic iron oxide nanoparticles (SPION) (10 nm in diameter) dispersed in distilled water at various concentrations. The measured diamagnetic repelling velocities correlated with our prediction and also with the magnetic susceptibility of the SPION solution measured by a SQUID magnetometer. Via this approach, we could determine the magnetic susceptibility of the subtle paramagnetic solution of GD-DTPA that could not be measured via the conventional method. This study provides us with the new capability of analyzing weakly paramagnetic solutions such as paramagnetic components or metal contaminants present in environmental liquid samples at low concentrations.

Synthesis and Biological Evaluation of a Novel Glucosylated Derivative of Gadolinium Diethylenetriaminepentaacetic Acid for Tumor Magnetic Resonance Imaging.

Cancer detection in early stage using a powerful and noninvasive tool is of high global interest. In this experiment, a small-molecular-weight glucose based derivative of Gd3+-1-(4-isothiocyanatobenzyl) diethylene tri amine penta acetic acid (Gd3+-p-SCN-Bn-DTPA-DG) as a novel potential MR imaging contrast agents was synthesized. Gd3+-p-SCN-Bn-DTPA-DG was synthesized with reacting of Glucosamine and 1-(4-isothiocyanatobenzyl) diethylene triamine penta acetic acid then loaded by gadolinium to make novel agent of functional MR imaging. The relaxivity, T 1, T 2 relaxation times, and cell toxicity of this contrast agent were studied. The results demonstrated that the sugar moieties linked to Gd3+-p-SCN-Bn-DTPA efficiently increase its cellular uptake in normal cells 25% and in cancereous cells upto 67%. The Gd3+-p-SCN-Bn-DTPA-DG significantly (p < 0.05) decreased MCF-7 tumor cell numbers without any significant toxicity on normal human kidney cells. Finally, it displayed an intense signal on T 1 weighted with respect to the unlabeled cells. Based on the findings from the present research Gd3+-p-SCN-Bn-DTPA-DG be a potential breast molecular imaging. However, further investigations by anticancer studies are in the pipeline.

Facile preparation of near-infrared fluorescence and magnetic resonance dual-modality imaging probes based on mesoporous organosilica nanoparticles

In this work, near-infrared fluorescence (NIRF) and magnetic resonance (MR) dual-modality imaging probes are prepared by conjugating maleimide derivative cyanine dye (Mal-Cy5.5), gadolinium‐diethylenetriamine pentaacetic acid (Gd-DTPA), and RGD peptide (Mal-PEG2-RGD) on thioether-bridged mesoporous organosilica nanoparticles (MONs) via click reaction. Fourier transform infrared (FT-IR) spectra, zeta potentials, UV–vis spectra, and energy dispersive X-ray (EDX) spectrum confirm the successful modifications of the functional molecules on the MONs. The prepared MON-Gd-Cy5.5-RGD probes shows excellent NIRF and MR imaging properties, and the relaxivity rate (r1) is measured up to 2.85 mM−1 s −1. In addition, the MON-Gd-Cy5.5-RGD probes show excellent in vitro and in vivo biocompatibility. Confocal laser scanning microscopy and flow cytometry demonstrate that the MON-Gd-Cy5.5-RGD can efficiently target to MDA-MB-231 tumor cells. Additionally, ex vivo NIFR and in vivo MR imaging demonstrate that the MON-Gd-Cy5.5-RGD probes can accumulate in tumor and improve the signals of tumor.

Optimization of delivering minimum Gd-DTPA at the posterior upper point on tympanic medial wall and hT2W-3D-FLAIR sequence for detecting endolymphatic hydrops

Objective: To optimize delivery of gadolinium-diethylenetriamine pentaacetic acid(Gd-DTPA) at the posterior upper point on tympanic medial wall and heavily T2-weighted 3-dimensional fluid-attenuated inversion recovery (hT2W-3D-FLAIR) sequence, and to implement the technique of detecting endolymphatic hydrops using gadolinium-enhancement MRI. Methods: Thirteen patients with periphery vertigo, who visited Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Changhai Hospital during June and December of 2017, were enrolled in the study.0.10-0.20 ml of Gd-DTPA in various dilutions (10, 20, and 40-fold) were delivered at the posterior upper point on tympanic medial wall using a soft-tipped tympanic suction and drug-spraying needle through an artificially perforated tympanic membrane. Inner ear MRI was performed at 8, 24 h after Gd-DTPA administration using a 3T MR machine in combination with a 20-channel Tim 4G head/neck coil and the sequence of hT2W-3D-FLAIR to detect the gadolinium-enhancement signal within the inner ear and possible endolymphatic hydrops. The scanning time was either 8 min 35 s or 15 min 11 s. Results: Efficient inner ear uptake of Gd-DTPA was detected and induced high signal to noise ratio of MRI in patients receiving targeted delivery of 0.15-0.20 ml of 10-fold diluted contrast agent at the posterior upper point on tympanic medial wall. At 8 h after delivery, significant uptake was detected in the scala tympani and vestibuli of hook region and basal turn of the cochlea, and perilymhatic compartment of the vestibule. At 24 h after delivery, the distribution of Gd-DTPA became homogenous in each turn of the cochlea and perilymphatic compartment of the vestibule. However, obvious individual variance existed in the inner ear uptake when 0.10 ml of 40-fold diluted Gd-DTPA was delivered. Efficient inner ear uptake and high quality images that generated in patients receiving 0.10, 0.15, and 0.20 ml of 20-fold Gd-DTPA demonstrated endolymphatic hydrops with minor individual variance. There was insignificant difference in the enhancement signal of inner ear between 0.15 and 0.10 ml groups when Gd-DTPA was diluted at 20-fold except for the signal of semicircular canal of 0.15 ml group (190.00±53.95 vs 165.50±42.13, t=2.61, P<0.05). There was insignificant difference in the image quality between 8 min 35 s and 15 min 11 s canning time. Various degrees of endolymphatic hydrops were detected in 7 cochleae and 11 vestibule, and both simultaneous cochlear and vestibular endolymphatic hydrops were detected in 4 ears. Cochlear endolymphatic hydrops was detected in all the 3 patients with definite Meniere's disease, and 2 of them had combined cochlear and vestibular endolymphatic hydrops. Endolymphatic hydrops was not detected in patients with possible Meniere's disease nor with symptoms of superior semicircular canal dehiscence. Conclusion: Targeted delivery of 0.10 ml with 20-fold diluted Gd-DTPA (total dosage of 5 μmol) at the posterior upper point on tympanic medial wall in combination with 8 min 35 s scanning time hT2W-3D-FLAIR sequence for inner ear MRI in a 3T MR machine is a clinically practical method to detect endolymphatic hydrops, and reduce the requirement for MRI hardware.

Spinal Cord Swelling After Surgery in Cervical Spondylotic Myelopathy: Relationship With Intramedullary Gd-DTPA Enhancement on MRI.

This is a prospective multicenter study. Postoperative spinal cord swelling has been reported in patients with cervical spondylotic myelopathy. In the cases of the spinal cord swelling, the involvement in the intramedullary gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement on magnetic resonance imaging (MRI) was referred. The prevalence and clinical relevance of postoperative spinal cord swelling and its relationship with intramedullary Gd-DTPA enhancement in patients with cervical spondylotic myelopathy were investigated. A total of 683 consecutive patients with cervical spondylotic myelopathy who underwent laminoplasty were examined. T1, T2, and Gd-DTPA-enhanced MRI were performed before surgery. Patients with intramedullary Gd-DTPA enhancement were allocated to the enhancement group. Fifty consecutive cases who did not exhibit intramedullary Gd-DTPA enhancement were allocated to the nonenhancement group. Both groups underwent MRI examinations at 1 month and 1 year after surgery. The prevalence of spinal cord swelling in the enhancement group (26%) was significantly higher than that in the nonenhancement group (4%) (P=0.0038). At 1 year after surgery, spinal cord swelling had resolved in all patients in the nonenhancement group, while it persisted in 3 of 13 patients (23%) in the enhancement group. On multiple regression analysis, intramedullary Gd-DTPA enhancement rather than the spinal cord swelling showed a significant influence in terms of recovery of the Japanese Orthopedic Association score. Surgical outcomes of patients with postoperative swelling should be evaluated separately according to the presence or absence of intramedullary Gd-DTPA enhancement on MRI. Spinal cord swelling associated with intramedullary Gd-DTPA enhancement was indicative of poor prognosis.

Biodegradable Nanoglobular Magnetic Resonance Imaging Contrast Agent Constructed with Host-Guest Self-Assembly for Tumor-Targeted Imaging.

Gadolinium-based macromolecular magnetic resonance imaging (MRI) contrast agents (CAs) have attracted increasing interest in tumor diagnosis. However, their practical application is potentially limited because the long-term retention of gadolinium ion in vivo will induce toxicity. Here, a nanoglobular MRI contrast agent (CA) PAMAM-PG- g-s-s-DOTA(Gd) + FA was designed and synthesized on the basis of the facile host-guest interaction between β-cyclodextrin and adamantane, which initiated the self-assembly of poly(glycerol) (PG) separately conjugated with gadolinium chelates by disulfide bonds and folic acid (FA) molecule onto the surface of poly(amidoamine) (PAMAM) dendrimer, finally realizing the biodegradability and targeting specificity. The nanoglobular CA has a higher longitudinal relaxivity ( r1) than commercial gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), showing a value of 8.39 mM-1 s-1 at 0.5 T, and presents favorable biocompatibility on the observations of cytotoxicity and tissue toxicity. Furthermore, MRI on cells and tumor-bearing mice both demonstrate the obvious targeting specificity, on the basis of which the effective contrast enhancement at tumor location was obtained. In addition, this CA exhibits the ability of cleavage to form free small-molecule gadolinium chelates and can realize minimal gadolinium retention in main organs and tissues after tumor detection. These results suggest that the biodegradable nanoglobular PAMAM-PG- g-s-s-DOTA(Gd) + FA can be a safe and efficient MRI CA for tumor diagnosis.

Visual targeted therapy of hepatic cancer using homing peptide modified calcium phosphate nanoparticles loading doxorubicin guided by T1 weighted MRI

Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02 mM−1 s−1) than commercial MR contrast agent Gd-DTPA (3.3765 mM−1 s−1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9-fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment.

Assessment of sequence dependent geometric distortion in contrast-enhanced MR images employed in stereotactic radiosurgery treatment planning

This work focuses on MR-related sequence dependent geometric distortions, which are associated with B0 inhomogeneity and patient-induced distortion (susceptibility differences and chemical shift effects), in MR images used in stereotactic radiosurgery (SRS) applications. Emphasis is put on characterizing distortion at target brain areas identified by gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) paramagnetic contrast agent uptake.A custom-made phantom for distortion detection was modified to accommodate two small cylindrical inserts, simulating small brain targets. The inserts were filled with Gd-DTPA solutions of various concentrations (0–20 mM). The phantom was scanned at 1.5 T unit using both the reversed read gradient polarity (to determine the overall distortion as reflected by the inserts centroid offset) and the field mapping (to determine B0 inhomogeneity related distortion in the vicinity of the inserts) techniques. Post-Gd patient images involving a total of 10 brain metastases/targets were also studied using a similar methodology.For the specific imaging conditions, contrast agent presence was found to evidently affect phantom insert position, with centroid offset extending up to 0.068 mm mM−1 (0.208 ppm mM−1). The Gd-DTPA induced distortion in patient images was of the order of 0.5 mm for the MRI protocol used, in agreement with the phantom results. Total localization uncertainty of metastases-targets in patient images ranged from 0.35 mm to 0.87 mm, depending on target location, with an average value of 0.54 mm (2.24 ppm). This relative wide range of target localization uncertainty results from the fact that the B0 inhomogeneity distortion vector in a specific location may add to or partly counterbalance Gd-DTPA induced distortion, thus increasing or decreasing, respectively, the total sequence dependent distortion.Although relatively small, the sequence dependent distortion in Gd-DTPA enhanced brain images can be easily taken into account for SRS treatment planning and target definition purposes by carefully inspecting both the forward and reversed polarity series.

Inhibition of Nox-1 Activity Attenuates Diabetic Ketoacidosis-Induced Blood Brain Barrier Permeability and Edema Formation

Diabetic ketoacidosis (DKA) is a condition characterized by hyperglycemia and high ketone bodies production conducting to acidosis. DKA is highly prevalent in pediatric patients. Approximately 0.5%-1% of these children develop cerebral edema, with a mortality rate of 20-90%. Our research examined the effects of DKA in Blood Brain Barrier (BBB) permeability using Ins2Akita mice as a T1D model. Using magnetic resonance (MR)-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA) we observed BBB permeability and fluid accumulation in the brain, during DKA episodes from day 1 to 5. Our data indicated that increased BBB permeability was present in the thalamus, partial cortex and basal forebrai. Furthermore, the analysis of the morphological and functional changes of BBB under DKA conditions both in vitro and in vivo in vitro showed alterations in TJ proteins, manifested as a slight alteration in ZO-1 and Claudin-5 expression which could represent the ground for BBB leakage. We have further identified that DKA promotes the high production of ROS due to Nox-1 activation, leading to actin reorganization, the subsequent TJ disorganization and increased BBB permeability. The inhibition of Nox-1 activity via Nox-1 inhibitor ML-17 improved the BBB integrity and reduced leakage. Collectively, these studies will provide new information related to novel therapeutic strategies to prevent or reverse vascular hyperpermeability in DKA. Disclosure G. Martinez-Revollar: None.

Effect of Mg and Ca on the Stability of the MRI Contrast Agent Gd–DTPA in Seawater

Gadolinium diethylenetriaminepentaacetic acid (Gd–DTPA) is widely applied as a contrast enhancer in medical MRI. As Gd–DTPA is only minimally captured in wastewater treatment plants (WTPs) or degraded by UV light and other oxidative processes, concentrations in rivers have increased globally by orders of magnitude following its introduction in 1987. The complex also seems impervious to estuarine scavenging and is beginning to emerge in coastal waters, yet it is unknown how its stability is changed by competition for the DTPA ligand from major seawater cations. We performed potentiometric titrations at seawater ionic strength (0.7 M NaClO4) to determine dissociation constants of the five DTPA carboxylic acid groups, as well as stability constants of Mg, Ca, and Gd complexes with the fully deprotonated and single-protonated ligand. These are in general agreement with literature values at low ionic strength and confirm that complexes with Ca are more stable than with Mg. A new finding, that the DTPA complexes of Mg and Ca appear to be hydrolyzed at elevated pH, implies that their coordination in these chelates is less than hexadentate, enabling additional competition with Gd from dinuclear Mg and Ca species. Side-reaction coefficients for trace-metal-free seawater, calculated from our results, suggest that the higher abundance of Mg and Ca may significantly destabilize Gd–DTPA in coastal waters, causing dissociation and release of as much as 15% of the organically complexed Gd from the ligand. This effect could enhance the particle-reactivity and bioavailability of anthropogenic Gd in sensitive estuarine habitats, indicating an urgent need to further study the fate of this contaminant in marine environments.

Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI).

To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI). pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTRasym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas. Simulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2 = 6.2 mM-1 ·sec-1 and R2* = 6.9 mM-1 ·sec-1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R2 (R2 = 0.9943) and multi-echo gradient-echo estimates of R2* (R2 = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , indicating high hypoxia and acidity. The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T.

Preclinical Animal Studies of Intravesical Recombinant Human Proteoglycan 4 as a Novel Potential Therapy for Diseases Resulting From Increased Bladder Permeability

To test in an animal model the hypothesis that recombinant human proteoglycan 4 (rhPRG4; lubricin), a highly O-glycosylated mucin-like glycoprotein, may be a novel surface-active therapeutic for treating bladder permeability with comorbid bowel permeability. Previously we showed that inducing bladder permeability in rats with dilute protamine sulfate (PS) produced colonic permeability and visceral hypersensitivity, suggesting increased bladder permeability could represent an etiologic factor in both interstitial cystitis-bladder pain syndrome and irritable bowel syndrome. We used an animal model of catheterized ovariectomized female rats instilled intravesically with 1 mg/mL PS for 10 minutes that after 24 hours were treated with 1.2 mg/mL lubricin or with vehicle alone. After 24 hours the bladder and colon were removed and permeability assessed electrophysiologically with the Ussing chamber to measure the transepithelial electrical resistance. A second set of rats was treated identically, except permeability was assessed on day 3 and on day 5 using contrast-enhanced magnetic resonance imaging with gadolinium diethylenetriamine penta-acetic acid instilled into the bladder. Intravesical lubricin reversed bladder permeability induced by PS and prevented the concomitant increase in permeability induced in the bowel (organ crosstalk). The protective effect was confirmed with magnetic resonance imaging, and because individual rats could be followed over time, the impermeability of the bladder restored by rhPRG4 remained for 5 days. These data indicate that instillation of rhPRG4 into a permeable bladder can restore its normally impermeable state, and that the effect lasts for 5 days and also prevents bowel symptoms often comorbid with interstitial cystitis-bladder pain syndrome.

Early animal model evaluation of an implantable contrast agent to enhance magnetic resonance imaging of arterial bypass vein grafts.

Background Non-invasive monitoring of autologous vein graft (VG) bypass grafts is largely limited to detecting late luminal narrowing. Although magnetic resonance imaging (MRI) delineates vein graft intima, media, and adventitia, which may detect early failure, the scan time required to achieve sufficient resolution is at present impractical. Purpose To study VG visualization enhancement invivo and delineate whether a covalently attached MRI contrast agent would enable quicker longitudinal imaging of the VG wall. Material and Methods Sixteen 12-week-old male C57BL/6J mice underwent carotid interposition vein grafting. The inferior vena cava of nine donor mice was treated with a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based contrast agent, with control VGs labeled with a vehicle. T1-weighted (T1W) MRI was performed serially at postoperative weeks 1, 4, 12, and 20. A portion of animals was sacrificed for histopathology following each imaging time point. Results MRI signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher for treated VGs in the first three time points (1.73 × higher SNR, P = 0.0006, and 5.83 × higher CNR at the first time point, P = 0.0006). However, MRI signal enhancement decreased consistently in the study period, to 1.29 × higher SNR and 2.64 × higher CNR, by the final time point. There were no apparent differences in graft morphometric analyses in Masson's trichrome-stained sections. Conclusion A MRI contrast agent that binds covalently to the VG wall provides significant increase in T1W MRI signal with no observed adverse effects in a mouse model. Further optimization of the contrast agent to enhance its durability is required.