Gadolinium Diethylenetriaminepentaacetate Research Articles

Feasibility Analysis of Brain Perfusion Using Polyaspartic Acid Surface-Modified Superparamagnetic Contrast Agent

This research was aimed to construct polyaspartic acid (PASP) surface-modified magnetic resonance imaging (MRI) contrast agent nanoparticles (NPs) and preliminarily demonstrate the feasibility of using the NPs for MRI cerebral perfusion. Ultrasmall superparamagnetic iron oxide (USPIO) NPs were fabricated by a one-step chemical coprecipitation methodology, and surface modification of USPIO NPs was performed using PASP as the surface modifier to prepare PASP-USPIO NPs. The physicochemical properties of the NPs were detected, and their specific structural ability with HUVECs was visualized by Prussian blue staining. With the contrast agent gadolinium-diethylene triamine pentaacetate (Gd-DTPA) as the control group, the intravenous bolus of USPIO and PASP-USPIO was analyzed and a brain MRI scan of New Zealand white rabbits was performed. The relative cerebral blood volume (rCBV) and maximum signal reduction ratio (SRRmax) values of cerebral gray matter and white matter were calculated based on the plotted time-signal intensity. The results showed that the USPIO and PASP-USPIO NPs were successfully prepared. The average particle sizes were 40.1±5.5 nm and 42.7±6.9 nm, respectively, and the specific saturation magnetization was 86.9 A m2 ·kg−1 and 51.3 A m2 ·kg−1, respectively. Relative to USPIO, human umbilical vein endothelial cells (HUVECs) stained with Prussian blue positively in vitro in the PASP-USPIO group were notably increased, while the rate of change in the signal-to-noise ratio of imaging in vivo was substantially decreased. The time-signal intensity curves were plotted, and it was found that the rCBV of gray matter, rCBV of white matter, SRRmax of gray matter, and SRRmax of white matter in the USPIO group and PASP-USPIO group were greatly increased relative to control group (P < 0.05), while the SRRmax ratio of gray matter to white matter was decreased (P < 0.05). Additionally, the rCBV in the gray matter and rCBV in the white matter of the PASP-USPIO group were drastically increased in contrast to the USPIO group (P < 0.05). In short, the constructed PASP surface-modified USPIO NPs can become a novel MRI contrast agent for monitoring hemodynamic changes in brain tissue.

Improving Vascular Functions by Bioreactive Nanoparticles for Treatment of Alzheimer’s Disease

AbstractBackgroundDeveloping effective disease‐modifying treatment for Alzheimer’s disease (AD) remains a tremendous challenge due to its multifactorial nature involving multiple pathologic signaling pathways in addition to ineffective drug delivery through the blood‐brain barrier (BBB).1 With this in mind our group has developed multifunctional bioreactive nanoparticles (Ab‐TP‐MDNPs), consisting of anti‐amyloid β antibody (Ab) linked to brain‐penetrating terpolymer (TP) and manganese dioxide (MnO2) nanoparticles (MDNPs), that are shown to reduce oxidative stress in AD brains.2 Given the early occurrence of oxidative stress, hypoxia, and vascular dysfunction in AD brains,3,4 we investigated the therapeutic effects of Ab‐TP‐MDNPs on reducing neuroinflammation and vascular dysfunction in an AD mouse model.MethodA transgenic mouse model of AD (TgCRND8 species) and wildtype littermates (WT) were treated with intravenous (i.v.) injection of Ab‐TP‐MDNPs (twice/week, 100 µmol Mn/kg b.w.) or vehicle for 2‐weeks. Oxidative and inflammatory biomarkers were examined using immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA). Vascular function before and after the treatment was studied via high resolution magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was assessed using FAIR (flow‐sensitive alternating inversion recovery) technique. BBB permeability was measured via T1 mapping re‐acquisition prior to and following i.v. injection of gadolinium‐diethylenetriamine penta‐acetate (Gd‐DTPA) at 1.2 mmol/kgResultAb‐TP‐MDNPs treatment significantly decreased inflammatory cytokines and activation of microglia and astrocytes markers (reactive microglia: hippocampus by 69% and cortex by 59%, reactive astrocytes: hippocampus by 32% and cortex by 33%). In addition, Ab‐TP‐MDNPs treatment improved CBF (cortex by 19% and subcortex by 35%) and vessel leakage by 29% in the cortex of AD mouse brains.ConclusionAb‐TP‐MDNPs treatment reduced neuroinflammation and vascular dysfunction in an AD mouse model. These findings suggest a new multimodal strategy for AD treatment and encourage further development of such approach for complex neurologic diseases.Reference:1. Panza F, Lozupone M, Logroscino G, Imbimbo BP. Nature Reviews Neurology. 2019;15(2):73‐88.2. He C, Ahmed T, Abbasi AZ, et al. Nano Today. 2020;35:100965.3. Sweeney MD, Montagne A, Sagare AP, et al. Alzheimer’s & Dementia. 2019;15(1):158‐167.4. Nortley R, Korte N, Izquierdo P, et al. Science. 2019:eaav9518.

Gadolinium-Coated Mesoporous Silica Nanoparticle for Magnetic Resonance Imaging.

Magnetic resonance molecular imaging can provide anatomic, functional and molecular information. However, because of the intrinsically low sensitivity of magnetic resonance imaging (MRI), high-performance MRI contrast agents are required to generate powerful image information for image diagnosis. Herein, we describe a novel T 1 contrast agent with magnetic-imaging properties facilitated by the gadolinium oxide (Gd2O3) doping of mesoporous silica nanoparticles (MSN). The size, morphology, composition, MRI relaxivity (r 1 ), surface area and pore size of these nanoparticles were evaluated following their conjugation with Gd2O3 to produce Gd2O3@MSN. This unique structure led to a significant enhancement in T 1 contrast with longitudinal relaxivity (r 1 ) as high as 51.85 ± 1.38 mM−1s−1. Gd2O3@MSN has a larger T 1 relaxivity than commercial gadolinium diethylene triamine pentaacetate (Gd-DTPA), likely due to the geometrical confinement effect of silica nanoparticles. These results suggest that we could successfully prepare a novel high-performance T 1 contrast agent, which may be a potential candidate for in-vivo MRI.

Expression of human serum albumin in Pichia pastoris protease-deficient host and conjugation with gadolinium-diethylenetriamine pentaacetate for application as a contrast agent

Expression of human serum albumin in Pichia pastoris protease-deficient host and conjugation with gadolinium-diethylenetriamine pentaacetate for application as a contrast agent

In vivo and ex vivo assessment of bladder hyper-permeability and using molecular targeted magnetic resonance imaging to detect claudin-2 in a mouse model for interstitial cystitis.

To determine if the URO-MCP-1 mouse model for bladder IC/BPS is associated with in vivo bladder hyper-permeability, as measured by contrast-enhanced MRI (CE-MRI), and assess whether molecular-targeted MRI (mt-MRI) can visualize in vivo claudin-2 expression as a result of bladder hyper-permeability. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, painful condition of the bladder that affects primarily women. It is known that permeability plays a substantial role in IC/BPS. Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. Claudin-2 is a molecular marker that is associated with increased hyperpermeability in the urothelium. CE-MRI was used to measure bladder hyper-permeability in the URO-MCP-1 mice. A claudin-2-specific mt-MRI probe was used to assess in vivo levels of claudin-2. The mt-MRI probe consists of an antibody against claudin-2 conjugated to albumin that had Gd-DTPA (gadolinium diethylenetriamine pentaacetate) and biotin attached. Verification of the presence of the mt-MRI probe was done by targeting the biotin moiety for the probe with streptavidin-horse radish peroxidase (SA-HRP). Trans-epithelial electrical resistance (TEER) was also used to assess bladder permeability. The URO-MCP-1 mouse model for IC/BPS was found to have a significant increase in bladder permeability, following liposaccharide (LPS) exposure, compared to saline-treated controls. mt-MRI- and histologically-detectable levels of the claudin-2 probe were found to increase with LPS -induced bladder urothelial hyper-permeability in the URO-MCP-1 IC mouse model. Levels of protein expression for claudin-2 were confirmed with immunohistochemistry and immunofluorescence imaging. Claudin-2 was also found to highly co-localize with zonula occlidens-1 (ZO-1), a tight junction protein. The combination of CE-MRI and TEER approaches were able to demonstrate hyper-permeability, a known feature associated with some IC/BPS patients, in the LPS-exposed URO-MCP-1 mouse model. This MRI approach could be clinically translated to establish which IC/BPS patients have bladder hyper-permeability and help determine therapeutic options. In addition, the in vivo molecular-targeted imaging approach can provide invaluable information to enhance our understanding associated with bladder urothelium hyper-permeability in IC/BPS patients, and perhaps be used to assist in developing further therapeutic strategies.

Nanoassembly and Multiscale Computation of Multifunctional Optical-Magnetic Nanoprobes for Tumor-Targeted Theranostics.

Gold nanorods, mesoporous silica, gadolinia, folic acid, and polyethylene glycol (PEG) derivatives have been investigated due to their own advantages in cancer theranostics. However, it remains a great challenge to assemble these components into a stable unity with the diverse and enhanced functionality for more potential applications. Herein, as inspired by the first-principles calculation, a highly stable and safe all-in-one nanoprobe is fabricated via a novel nanoassembly strategy. Multiscale calculations were performed to address the atomistic bonding of a nanoprobe, heat necrosis of a tumor adjacent to the vasculature, and thermal diffusion in a photothermal circumstance, respectively. The nanoprobe gains an 8-fold increase in magnetic resonance imaging (MRI) relaxivity compared to the clinical gadolinium diethylenetriaminepentaacetate, achieving a significant MRI signal in vivo. Conjugated with folate-PEG, the nanoprobe can be effectively absorbed by tumoral cells, obtaining a vivid two-photon cell imaging. A specific multisite scheme for photothermal therapy of a solid tumor is proposed to improve low photothermal efficacy caused by thermal diffusion in a large tumor, leading to the successful cure of the mice with xenograft tumor sized 10-12 mm. In vitro and in vivo toxicity, long-term excretion data, and the recovery of the treated mice demonstrate that the theranostic nanoprobe possesses good biocompatibility and metabolism efficacy.

Understanding the High Longitudinal Relaxivity of Gd(DTPA)-Intercalated (Zn,Al)-Layered Double Hydroxide Nanoparticles.

In this study, biocompatible gadolinium diethylenetriaminepentaacetate (Gd(DTPA))-intercalated (Zn,Al)-layered double hydroxide (LDH) nanoparticles were synthesized, characterized for Gd(DTPA) loading percentage and nanostructure, and the spin-lattice relaxation times (T1) measured to determine their suitability as a potential T1-weighted contrast agent for magnetic resonance imaging (MRI). Compared to the most commonly used contrast agent in clinical MRI (i.e., molecular Gd(DTPA)), significant increases in longitudinal relaxivity (r1) were measured for all Gd(DTPA)-intercalated nanoparticles. For a specific Zn2Al(OH)6(Cl,0.5CO3)0.56Gd(DTPA)0.086·xH2O composition, r1 was found to be 28.38 s-1 mM-1, which is over 6 times the r1 of molecular Gd(DTPA). This dramatic increase in r1 is attributed to (a) the much longer rotational correlation time (τR) of nanoparticles and (b) the inherent water of LDH that forms the second-/outer-sphere in the vicinity of intercalated Gd(DTPA)2-. The latter, with an extensive hydrogen bonding network and insignificant translational motion, results in a longer mean residence lifetime (τM), which makes the contribution of second-/outer-sphere significant. Therefore, when the Gd(DTPA)2- loading percentage increases from 8.6 to 55%, the diminution of the ratio of inherent water to Gd(DTPA)2- concomitantly diminishes the contributions by second-/outer-sphere water to r1. Additionally, the modest increase in r1 with decreasing particle size (∼315-540 nm) is perhaps due to the shortening of τM. Finally, the spin-spin relaxation times (T2) of 17O, determined at various temperatures, show a negligible exchange of water molecules at room temperature. Therefore, the very high r1 of nanoparticles indicate that protons of the bulk water are still accessible to the Gd3+ centers, possibly dominated by prototropic exchange through the hydrogen bonding network.

Iopromide- and gadopentetic acid-derived preparates used in MR arthrography may be harmful to chondrocytes

BackgroundMagnetic resonance arthrography, a procedure through which contrast agents containing gadolinium and/or iopromide are administered intra-articularly, has become a useful tool in musculoskeletal diagnosis. Nevertheless, despite being considered safe for systemic use, certain tissue toxicities have been identified for both drugs. In this study, the effects of short-term exposure of human primary chondrocyte cell cultures to gadolinium and/or iopromide contrast agents were examined by assaying for stage-specific embryonic antigen-1 (SSEA-1) protein expression (a chondrogenic differentiation marker), cell viability, toxicity, and proliferation.MethodsHuman articular chondrocytes were grown in monolayer culture and were exposed to iopromide and/or gadolinium diethylenetriamine-pentaacetate (Gd-DPT) for 2 and 6 h. Cell cultures with no drug exposure were used as the control group. Cell differentiation status was assessed according to SSEA-1 protein expression. Contrast agent effects on cell viability and proliferation were analyzed using MTT analysis. Further, changes in cell morphology in relation to the control group were evaluated using inverted light microscopy, environmental scanning electron microscopy (ESEM), and 3-tesla magnetic resonance imaging. The obtained data were statistically compared.ResultsWhen compared with the control group, both SSEA-1 protein expression and cell proliferation were lowest in the Gd-DPT group (P = 0.000). There was a statistically significant correlation between SSEA-1 expression and MTT results (rho = 0.351; P = 0.003).ConclusionsNevertheless, the data obtained from in vitro experiments may not directly correspond to clinical applications. However, the mere fact that a drug used solely for diagnostic purposes may repress chondrocyte cell proliferation should be carefully considered by clinicians.

Prostate cancer targeted multifunctionalized graphene oxide for magnetic resonance imaging and drug delivery

Dendrimers capped with amino groups (DEN) are grafted to graphene oxide (GO) nanosheets for subsequent functionalization of GO with gadolinium diethylene triamine pentaacetate (Gd-DTPA) and prostate stem cell antigen (PSCA) monoclonal antibody (mAb). The as-prepared GO-DEN(Gd-DTPA)-mAb exhibits very low cytotoxicity, negligible hemolytic activity, and no perceptible toxic effects in mice. GO-DEN(Gd-DTPA)-mAb can specifically target PSCA over-expressed cancer cells to give a significant T1-weighted contrast enhancement effect. The in vivo magnetic resonance imaging results indicate that GO-DEN(Gd-DTPA)-mAb can be used as a targeted contrast agent for prostate tumor imaging. GO-DEN(Gd-DTPA)-mAb can be efficiently loaded with doxorubicin hydrochloride (DOX), and the resulting GO-DEN(Gd-DTPA)-mAb/DOX exhibits enhanced cytotoxicity to PC-3 cells due to good targeting performance. By following the PC-3 tumor growth in mouse model after intravenous administration of GO-DEN(Gd-DTPA)-mAb/DOX, it is demonstrated that GO-DEN(Gd-DTPA)-mAb can targetedly deliver anticancer drugs to malignant prostate tumors and inhibit tumor growth.

Coupling Gd‑DTPA with a bispecific, recombinant protein anti‑EGFR‑iRGD complex improves tumor targeting in MRI.

Recombinant anti-epidermal growth factor receptor-internalizing arginine-glycine-aspartic acid (anti-EGFR single-domain antibody fused with iRGD peptide) protein efficiently targets the EGFR extracellular domain and integrin αvβ/β5, and shows a high penetration into cells. Thus, this protein may improve penetration of conjugated drugs into the deep zone of gastric cancer multicellular 3D spheroids. In the present study, a novel tumor-targeting contrast agent for magnetic resonance imaging (MRI) was developed, by coupling gadolinium-diethylene triamine pentaacetate (Gd-DTPA) with the bispecific recombinant anti-EGFR-iRGD protein. The anti-EGFR-iRGD protein was extracted from Escherichia coli and Gd was loaded onto the recombinant protein by chelation using DTPA anhydride. Single-targeting agent anti-EGFR-DTPA-Gd, which served as the control, was also prepared. The results of the present study showed that anti-EGFR-iRGD-DTPA-Gd exhibited no significant cyto toxicity to human gastric carcinoma cells (BGC-823) under the experimental conditions used. Compared with a conventional contrast agent (Magnevist), anti-EGFR-iRGD-DTPA-Gd showed higher T1 relaxivity (10.157/mM/sec at 3T) and better tumor-targeting ability. In addition, the signal intensity and the area under curve for the enhanced signal time in tumor, in vivo, were stronger than Gd-DTPA alone or the anti-EGFR-Gd control. Thus, Gd-labelled anti-EGFR-iRGD has potential as a tumor-targeting contrast agent for improved MRI.

Electrospun Contrast-Agent-Loaded Fibers for Colon-Targeted MRI.

Magnetic resonance imaging is a diagnostic tool used for detecting abnormal organs and tissues, often using Gd(III) complexes as contrast-enhancing agents. In this work, core-shell polymer fibers have been prepared using coaxial electrospinning, with the intent of delivering gadolinium (III) diethylenetriaminepentaacetate hydrate (Gd(DTPA)) selectively to the colon. The fibers comprise a poly(ethylene oxide) (PEO) core loaded with Gd(DTPA), and a Eudragit S100 shell. They are homogeneous, with distinct core-shell phases. The components in the fibers are dispersed in an amorphous fashion. The proton relaxivities of Gd(DTPA) are preserved after electrospinning. To permit easy visualization of the release of the active ingredient from the fibers, analogous materials are prepared loaded with the dye rhodamine B. Very little release is seen in a pH 1.0 buffer, while sustained release is seen at pH 7.4. The fibers thus have the potential to selectively deliver Gd(DTPA) to the colon. Mucoadhesion studies reveal there are strong adhesive forces between porcine colon mucosa and PEO from the core, and the dye-loaded fibers can be successfully used to image the porcine colon wall. The electrospun core-shell fibers prepared in this work can thus be developed as advanced functional materials for effective imaging of colonic abnormalities.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging.

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new noninvasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (iv) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.

Magnetic resonance imaging of intraductal papillomas: typical findings and differential diagnosis.

Even upon core biopsy, accurate classification of benign intraductal papillomas (IPs) can be difficult. Accordingly, IPs are still frequently surgically resected. Therefore, accurate classification of IP by magnetic resonance mammography (MRM) would potentially optimize patient management. However, the few investigations assessing MRM of IP included small patient collectives, and overall accuracy is still unknown. We performed this investigation to analyze the morphologic and dynamic MRM profiles of IP in more detail and to identify the overall accuracy of MRM for differential diagnosis of IP versus malignant breast lesions. Consecutive patients scheduled for MRM (standardized scanning protocols: dynamic T1-weighted gradient echo before/after Gd-DTPA [gadolinium diethylenetriamine pentaacetate; 0.1 mmol/kg body weight]; T2-weighted turbo spin echo) with subsequent surgicopathologic verification were enrolled. For the detailed assessment of morphologic and dynamic profiles, 2 experienced radiologists (>500 MRM examinations; blinded to surgicopathologic verification) performed prospective evaluation of MRM, in consensus, applying 17 predefined MRM descriptors. From this database, all patients showing IP (n = 83) or malignant breast lesions (n = 648) were further evaluated statistically: univariate analyses (association of single descriptors with IP/breast cancer: contingency table statistics) and multivariate analyses were performed to identify accurate descriptor combinations (CHAID [CHi-squared Automatic Interaction Detection]) and overall accuracy of MRM for differential diagnosis of IP versus malignant breast lesions (logistic regression; receiver operating characteristics [ROC], area under the ROC curve). There were 82.4% of MRM descriptors significantly associated with IP (n = 14; P < 0.05). The accuracy of single descriptors (odds ratio [OR], ≤10.6) could be further increased by descriptor combinations (double combination: OR ≤12.7; triple combination: OR ≤15.0). With area under the ROC curve = 0.90, there was a high overall accuracy of MRM for the differential diagnosis of IP versus malignant breast lesions. A detailed assessment of MRM allows precise characterization of benign IPs and accurate differentiation from malignant breast lesions.

An MRI-sensitive, non-photobleachable porphysome photothermal agent.

Photothermal therapy makes use of photothermal sensitizers and laser light to thermally ablate diseased tissues. Porphysome nanoparticles offer a nontoxic alternative to inorganic nanocrystals for the efficient conversion of light into heat. Mn(3+) ions were incorporated directly into the building blocks of our porphysome nanoparticles, thus imparting MRI sensitivity while simultaneously improving photostability and maintaining high photothermal efficiency. Mn porphysomes are as photothermally effective as free-base porphysomes and can rival gadolinium diethylenetriaminepentaacetate (Gd-DTPA) for MRI contrast generation. Their MRI contrast generation, photothermal efficiency, and photostability are unprecedented for an all-organic nanoparticle composed of a single functional component.

An MRI‐Sensitive, Non‐Photobleachable Porphysome Photothermal Agent

AbstractPhotothermal therapy makes use of photothermal sensitizers and laser light to thermally ablate diseased tissues. Porphysome nanoparticles offer a nontoxic alternative to inorganic nanocrystals for the efficient conversion of light into heat. Mn3+ ions were incorporated directly into the building blocks of our porphysome nanoparticles, thus imparting MRI sensitivity while simultaneously improving photostability and maintaining high photothermal efficiency. Mn porphysomes are as photothermally effective as free‐base porphysomes and can rival gadolinium diethylenetriaminepentaacetate (Gd‐DTPA) for MRI contrast generation. Their MRI contrast generation, photothermal efficiency, and photostability are unprecedented for an all‐organic nanoparticle composed of a single functional component.

Modulation of Blood–Brain Barrier Permeability in Mice Using Synthetic E-Cadherin Peptide

The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood–brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3–6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents.

Contrast agents for MRI: 30+ years and where are we going?

Thirty years ago, Schering filed the first patent application for a contrast agent for magnetic resonance imaging (MRI) covering the forefather of the gadolinium contrast agents and still the most widely used gadolinium probe: gadolinium(III) diethylenetriaminepentaacetate (Magnevist). To date, 11 contrast agents have been approved by the US Food and Drug Administration for intravenous use. Coordination chemists have done a great deal to move the field forward. Our understanding of lanthanide chemistry now makes possible the design of complexes with long rotational correlation times, fast or slow water-exchange rates, high thermodynamic stabilities, and kinetic inertness, leading to sensitive and nontoxic contrast agents. Chemists did not stop there. The last few decades has seen the development of novel classes of probes that yield contrast through different mechanisms, such as paramagnetic chemical exchange saturation transfer agents. Thirty years since the first patent, chemists are still leading the way. The development of high-sensitivity contrast agents for high magnetic fields, safe probes for patients with kidney disorders, and multimodal, targeted, and responsive agents demonstrates that the field of contrast agents for MRI still has much to offer.

Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.

Perfusion deficits in patients with mild traumatic brain injury characterized by dynamic susceptibility contrast MRI

Perfusion deficits in patients with mild traumatic brain injury (TBI) from a military population were characterized by dynamic susceptibility contrast perfusion imaging. Relative cerebral blood flow (rCBF) was calculated by a model-independent deconvolution approach from the tracer concentration curves following a bolus injection of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) using both manually and automatically selected arterial input functions (AIFs). Linear regression analysis of the mean values of rCBF from selected regions of interest showed a very good agreement between the two approaches, with a regression coefficient of R = 0.88 and a slope of 0.88. The Bland-Altman plot also illustrated the good agreement between the two approaches, with a mean difference of 0.6 ± 12.4 mL/100 g/min. Voxelwise analysis of rCBF maps from both approaches demonstrated multiple clusters of decreased perfusion (p < 0.01) in the cerebellum, cuneus, cingulate and temporal gyrus in the group with mild TBI relative to the controls. MRI perfusion deficits in the cerebellum and anterior cingulate also correlated (p < 0.01) with neurocognitive results, including the mean reaction time in the Automated Neuropsychological Assessment Metrics and commission error and detection T-scores in the Continuous Performance Test, as well as neurobehavioral scores in the Post-traumatic Stress Disorder Checklist-Civilian Version. In conclusion, rCBF calculated using AIFs selected from an automated approach demonstrated a good agreement with the corresponding results using manually selected AIFs. Group analysis of patients with mild TBI from a military population demonstrated scattered perfusion deficits, which showed significant correlations with measures of verbal memory, speed of reaction time and self-report of stress symptoms.

Carbon-13 nuclear magnetic resonance analysis of formaldehyde free preservatives

Preservation of biomolecules is pivotal in increasingly important molecular diagnostics. Traditionally, formaldehyde is employed for such biomolecular preservation in spite of its carcinogenicity. Moreover, formaldehyde induced cross-linking during fixation is reported to alter structural and functional properties of the preserved biomolecules. Therefore, formaldehyde-free preservatives are advantageous because they are safer for laboratory personnel and they protect the structural and functional integrity of the biomolecules. Streck Cell Preservative and Cell-Free DNA BCT reagents are used as formaldehyde alternative preservatives. However, no studies have been carried out to evaluate formaldehyde concentrations in these preservatives. In this study, we evaluated the free formaldehyde concentrations of these reagents by carbon-13 (13C) NMR spectroscopic analysis. Chemically non-invasive NMR analysis is more reliable than the traditional derivatization based techniques in formaldehyde detection. 13C NMR technique can be used for quantitative measurement by using 13C NMR-relaxation agents. In this manuscript, we report an optimized NMR analysis method using Gadolinium diethylenetriaminepentaacetate. Additionally the data reported herein provide spectral analyses that indicate Streck Cell Preservative and Cell-Free DNA BCT reagents do not contain detectable free formaldehyde. Therefore, these preservatives are safer alternatives than formaldehyde for laboratory use, which can protect the overall integrity of the biomolecules within preserved samples.