A new paramagnetically shifted imaging probe for MRI.

PURPOSE: To develop and characterize a new paramagnetic contrast agent for molecular imaging by MRI. METHODS: A contrast agent was developed for direct MRI detection through the paramagnetically shifted proton magnetic resonances of two chemically equivalent tert-butyl reporter groups within a dysprosium(III) complex. The complex was characterized in phantoms and imaged in physiologically intact mice at 7 Tesla (T) using three-dimensional (3D) gradient echo and spectroscopic imaging (MRSI) sequences to measure spatial distribution and signal frequency. RESULTS: The reporter protons reside ∼6.5 Å from the paramagnetic center, resulting in fast T1 relaxation (T1 = 8 ms) and a large paramagnetic frequency shift exceeding 60 ppm. Fast relaxation allowed short scan repetition times with high excitation flip angle, resulting in high sensitivity. The large dipolar shift allowed direct frequency selective excitation and acquisition of the dysprosium(III) complex, independent of the tissue water signal. The biokinetics of the complex were followed in vivo with a temporal resolution of 62 s following a single, low-dose intravenous injection. The lower concentration limit for detection was ∼23 µM. Through MRSI, the temperature dependence of the paramagnetic shift (0.28 ppm.K-1 ) was exploited to examine tissue temperature variation. CONCLUSIONS: These data demonstrate a new MRI agent with the potential for physiological monitoring by MRI. Magn Reson Med 77:1307-1317, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Dual responsive dysprosium-doped hydroxyapatite particles and toxicity reduction after functionalization with folic and glucuronic acids.

The development of probes for biomedical applications demands materials with low toxicity levels besides fluorescence or magnetic properties to be detected by confocal microscopes or MRI resonators. Several drug delivery systems or other biomedical materials prepared with hydroxyapatite have been proposed, however, toxicity effects might arise when the size of particles is nanometric. In this study, hydroxyapatite functionalized with glucuronic or folic acids presented lower oxidative stress, measured from lipoperoxides and nitric oxide indicators in rats than pure hydroxyapatite. In separated experiments, hydroxyapatite was doped with dysprosium cations by coprecipitation producing a single crystal phase with fluorescent properties easily visualized by confocal microscopy when excited at 488nm. These particles also presented the ability to modify the proton relaxation time in T1 maps collected by magnetic resonance imaging. These modified hydroxyapatite nanoparticles could be candidates to design bimodal probes with low toxicity.

Dietary inulin intake and age can significantly affect absorption of the faecal marker dysprosium in rats.

It is believed that rare earth elements are not absorbed, and thus they are generally used in some mineral absorption studies as a faecal marker. The aim of the present study was to determine the effect of inulin intake and age on dysprosium (Dy) absorption in rats. Eighty male Wistar rats of four different ages (2, 5, 10 and 20 months) were randomised into either a control group or a group receiving 3.75 % inulin in their diet for 4 d and then 7.5 % inulin until the end of the study. The animals were fed fresh food and water ad libitum for 30 d. The intestinal absorption of Dy was determined from a 4 d (day 21 to day 25) balance study. Mean faecal Dy recovery (%) in the eight groups (3 months control, 3 months inulin, 6 months control, 6 months inulin, 11 months control, 11 months inulin, 21 months control, 21 months inulin) was 94.0 (sd 8.6), 64.8 (sd 10.1), 95.8 (sd 9.4), 81.5 (sd 12.1), 98.4 (sd 9.8), 87.8 (sd 9.5), 97.8 (sd 6.2) and 84.9 (sd 10.9), respectively. Our results showed clearly that dietary inulin intake decreased faecal Dy recovery in all four rat groups, and faecal Dy recovery was significantly higher in the old rats (10 and 20 months) than in the young and adult rats. These results show that the faecal recovery (or intestinal absorption) of Dy may vary greatly with nutritional or physiological states such as inulin intake or age. The use of rare earth elements as a faecal marker should be thus validated under each nutritional or physiological state before being employed in mineral absorption studies.

[166Dy]Dy/166Ho hydroxide macroaggregates: an in vivo generator system for radiation synovectomy.

Radiation synovectomy is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. The aim of this work was to examine the feasibility of preparing dysprosium-166 (166Dy)/holmium-166(166Ho) hydroxide macroaggregates ([166Dy]Dy/166Ho-HM) as an in vivo generator for radiation synovectomy evaluating whether the stability of 166Dy-HM and 166Ho-HM complexes is maintained when the daughter 166Ho is formed. The Monte Carlo (MCNP4B) theoretical depth dose profile for the in vivo [166Dy]Dy/166Ho generator system in a joint model was calculated and compared with that produced by 90Y, 153Sm and 166Ho. 166Dy was obtained by neutron irradiation of enriched 164Dy2O3 in a Triga Mark III reactor. Macroaggregates were prepared by reaction of [166Dy]DyCl3 with 0.5 M NaOH in an ultrasonic bath. [166Dy]Dy/166Ho-HM was obtained with radiochemical purity >99.5% and with the majority of particles in the 2-5 microm range. In vitro studies demonstrated that the radio-macroaggregates are stable in saline solution and human serum without a significant change in the particle size over 14 d, suggesting that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biological studies in normal rats demonstrated high retention in the knee joint even 7 d after [166Dy]Dy/166Ho-HM administration. The Monte Carlo (MCNP4B) theoretical depth dose profiles in a joint model, showed that the in vivo [166Dy]Dy/166Ho generator system would produce 25% and 50% less radiation dose to the articular cartilage and bone surface, respectively, than that produced by 90Y or pure 166Ho in a treatment with the same therapeutic dose to the synovium surface. Despite that 153Sm showed the best depth dose profile sparing doses to healthy tissues, the use of 166Dy could provide the advantage of being applied in patients that cannot be reached within a few hours from a nuclear reactor and to produce less radiation exposure to the medical personnel during the radiopharmaceutical administration.

Dysprosium-bearing red cells as potential transverse relaxation agents for MRI.

The cytosol of intact human red blood cells was loaded with 28.1 +/- 3.4 mM of dysprosium DTPA-BMA using a hypoosmotic technique. When loaded cells were diluted with saline and control cells to give an average dysprosium concentration of 3.3 +/- 0.5 mM, the transverse relaxation rate constants R(*)(2) and R(2) increased. R(*)(2) increased from 7.5 +/- 0.9 sec(-1) to 356 +/- 50 sec(-1), and R(2) increased from 7.4 +/- 0.7 sec(-1) to 148 +/- 40 sec(-1). After lysing, R(*)(2) was 6.0 +/- 0.6 sec(-1) in the control and 13.4 +/- 1.5 sec(-1) in the mixture; R(2) was 6.4 +/- 1.1 sec(-1) and 9.8 +/- 2.4 sec(-1), respectively. Thus, the relaxivity effects were enhanced by sequestration of the dysprosium within intact red cells, and this effect was lost after lysis. At a circulating whole-blood concentration of 0.81 +/- 0.15 mM in rats, the liver signal intensity dropped 29.9% +/- 3.7% and kidney signal intensity dropped 19.4% +/- 8.7%. Dysprosium-loaded cells might be useful in the study of perfusion and tissue blood volume.

Monitoring of the biodistribution and biokinetics of dysprosium-165 ferric hydroxide with a shadow-shield whole-body counter.

Radiation synovectomy is indicated when conventional pharmacological treatment of chronic synovitis has proved insufficient. In these cases dysprosium-165 ferric hydroxide (DFH) has been demonstrated to be clinically effective. After application of the agent, blood activity measurements and monitoring of activity distribution by gamma camera imaging over the local lymph nodes and the liver are commonly performed for control of possible leakage. In addition, we have used a shadow-shield whole-body counter with a profile facility to evaluate the biokinetics and biodistribution of 165Dy-DFH. Fifteen intra-articular injections were performed in 13 patients who received a median activity of 6.8 GBq (range 0.5-9.9 GBq) 165Dy-DFH. Activity profiles were obtained with the whole-body counter 2, 4 and 6 h after injection of 165Dy-DFH. The doses to non-target organs were calculated using the software MIRDOSE 3. In 10 of 15 treatments, absence of any leakage could be demonstrated. The effect of scattered rays could be observed in 14 measurements. In three patients small amounts of activity could be detected in the urinary bladder and in three patients activity was detected in the local inguinal lymph nodes, while no leakage could be detected by camera imaging. In these cases the individual doses to the bladder were 15 Gy, 65 mGy and 50 mGy, and those to the lymph nodes, 0.54 Gy, 0.89 Gy and 2.41 Gy. The whole-body counter also enabled the monitoring of activity profiles related to more complex pathological structures. In conclusion, using a whole-body counter activity leakage could be detected with much higher sensitivity than by using a gamma camera. The biodistribution of 165Dy-DFH could be determined, and leakage could be localised and related to organs. These results encourage the use of a whole-body counter to identify the site and extent of activity leakage.

Low molecular weight lanthanide contrast agents: in vitro studies of mechanisms of action.

The MR contrast properties of a series of structurally dissimilar low molecular weight (LMW) gadolinium (Gd) and dysprosium (Dy) chelates have been investigated under controlled experimental conditions in various in vitro test systems. Relaxation analysis (water, pH = 5.8, 37 degrees C, .47 T) demonstrated the high dipolar relaxation efficacy of the tested Gd chelates. The T1 and T2 relaxivities of both metal chelate series decreased with decreasing hydration number, confirming the strong correlation between metal chelate structure and dipolar relaxivity. Susceptibility-induced T2 relaxation, commonly known as the susceptibility effect, is modulated primarily by the magnetic susceptibility and compartmentalization of the contrast agent. The influence of these parameters on the susceptibility effect of Dy diethylenetriamine penta-acetic acid bis-methylamide (DTPA-BMA) and GdDTPA-BMA was investigated in two-compartment in vitro models. In red blood cell suspensions (45% hematocrit, 37 degrees C, .47 T, 2 and 3 mM metal ion concentration), the T2 relaxation efficacy of DyDTPA-BMA was markedly improved due to susceptibility effects that were shown to depend on compartmentalization. As the relaxation ability of GdDTPA-BMA was modulated by the dipolar interactions, compartmentalization was not a prerequisite for its T2 relaxation efficacy. In a coaxial glass system with no intercompartmental water exchange, which eliminated the dipolar relaxation mechanism, DyDTPA-BMA was shown to be the most efficient susceptibility agent because of its higher magnetic susceptibility. The reported one- and two-compartment model studies have demonstrated the different mechanism of action of LMW Gd- and Dy-based contrast agents. Gd chelates are predominantly dipolar relaxation enhancers, whereas Dy chelates are efficient susceptibility agents only in compartmentalized systems.

Ytterbium- and dysprosium-EOB-DTPA. A new prototype of liver-specific contrast agents for computed tomography.

RATIONALE AND OBJECTIVES: A series of studies was conducted to determine whether metal complexes of the EOB-DTPA type are useful as contrast agents for computed tomography (CT). METHODS: Metal complexes using EOB-DTPA as ligand were synthesized with lanthanide metal ions (lanthanum [La], cerium [Ce], praseodyme [Pr], gadolinium [Gd], dysprosium [Dy], ytterbium [Yb], and lutetium [Lu]) and with nonlanthanides (lead [Pb] and bismuth [Bi]). Complex stability was assessed by measuring binding to bone meal. The physicochemical parameters partition coefficient, osmolality, viscosity, and protein binding were determined in vitro. Tolerability was tested both in vitro (thromboplastin time, effect on erythrocytes) and in vivo (acute, neural, and cardiovascular toxicities). Biliary excretion and tissue distribution, especially liver, kidney, and bone concentrations, were measured in rats after intravenous doses of 0.5 mmol/kg. Imaging performance using CT was investigated in vitro in a phantom model and, for Gd-EOB-DTPA, in vivo by injecting doses of 0.5 mmol/kg into healthy or tumor-bearing rats and rabbits. RESULTS: The kinetic stability of M-EOB-DTPA complexes differed widely. Nonlanthanide metals, especially Pb-EOB-DTPA, provided less stable complexes than lanthanides with an optimum of stability for the metals Gd, Dy, Yb, and Lu. Tolerability was good for all compounds, best results were obtained for Gd and Yb. Concentrations in rat liver after administration of Gd-EOB-DTPA, 0.5 mmol/kg intravenous, were approximately 1 mumol/g, resulting in CT enhancement of 16 Hounsfield units (HU). Tumor tissue was not enhanced. In rabbits, at the same dose level 30 HU was found. CONCLUSIONS: Metal complexes of the EOB-DTPA type, especially those of Gd and Yb seem to be useful as iodine-free liver-specific contrast agents for CT.

[166Dy]dysprosium/[166Ho]holmium in vivo generator.

A novel approach for the delivery of 166Ho (t1/2 = 26.6 h) to tissue is via the in vivo decay of its 81.5 h parent, 166Dy-an in vivo generator system. A critical question for the in vivo 166Dy/166Ho generator system is whether translocation of the daughter nucleus occurs. The in vitro and in vivo integrity of the [166Dy]Dy/166Ho-DTPA complex was investigated and results indicated that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biodistribution studies of [166Dy]Dy-DTPA showed that the ratio of 166Dy/166Ho in bone remains constant (+/- 7%) over a 20 h period, indicating no significant in vivo loss of 166Ho from the complex. Increasing the in vivo residence time of [166Dy]Dy-DTPA complex attached to HSA gave similar results.

MR imaging of double-contrast enhanced porcine myocardial infarction. Correlation with microdialysis.

MR imaging was performed to investigate whether Gd-DTPA-BMA-induced contrast enhancement of myocardial infarction is counteracted by Dy-DTPA-BMA. Myocardial infarction was induced in 5 pigs. Microdialysate probes were inserted in ischemic and nonischemic myocardium. Gd-DTPA-BMA (0.3 mmol/kg b.w.) and Dy-DTPA-BMA (1.0 mmol/kg b.w.) were administered i.v. 4 hours post occlusion. The microdialysate was collected every 10 min and measured for Gd and Dy using inductively coupled plasma atomic emission spectrometry. The pigs were sacrificed 2 hours after administration of contrast media. The concentration of both contrast agents was 3 times higher in infarcted myocardium than in nonischemic myocardium. The infarctions displayed high signal intensity in spin-echo sequences ex vivo. This lack of detectable susceptibility effects from Dy may be caused by loss of cell membrane integrity in infarcted tissue as shown by our microdialysate and biopsy data.

Dy-DTPA-BMA as an indicator of tissue viability in MR imaging. An experimental study in the pig.

The aim of this study was to investigate whether dysprosium (Dy) induced signal intensity (SI) loss in infarcted tissue in MR imaging. Myocardial infarction was induced in 12 pigs and Dy-DTPA-BMA (1.0 mmol/kg b.w.) was administered i.v. to 6 pigs 4 hours after occlusion and allowed to accumulate in the infarctions for 2 hours. Dy was analysed by inductively coupled plasma atomic emission spectrometry in infarcted and non-ischaemic tissue samples. The remaining 6 pigs, not administered contrast medium, served as controls. The infarctions demonstrated a high SI in the proton density- and T2-weighted sequences in both groups (ex vivo), although the Dy-DTPA-BMA group demonstrated a 3-fold greater concentration of Dy in infarcted compared with non-ischaemic myocardium. The lack of SI loss after Dy accumulation indicates that susceptibility effects are minor or absent in infarcted myocardium.

MR imaging of contrast-enhanced porcine myocardial infarction. Assessment of reperfusion and tissue viability.

To assess the usefulness of Dy-DTPA-BMA-induced signal reduction, as an indicator of myocardial viability, myocardial infarction was induced in 17 domestic pigs by ligating a diagonal branch of the left anterior descending coronary artery (LAD). In 6 pigs, Dy-DTPA-BMA (1 mmol/kg b.w.) was administered 4 hours after induction of ischaemia. In 5 additional pigs, Gd-DTPA-BMA (0.3 mmol/kg b.w.) and Dy-DTPA-BMA (1 mmol/kg b.w.) were simultaneously injected after 4 hours of ischaemia to ascertain whether Dy-DTPA-BMA counteracted the signal enhancement effect of Gd-DTPA-BMA. A further 6 pigs with infarctions, not administered contrast medium, served as controls. All pigs were sacrificed after 6 hours of ischaemia, and the extirpated hearts were investigated with MR (ex vivo). The concentrations of Dy and Gd were determined in tissue samples from infarcted and non-ischaemic myocardium. The extracellular concentrations of both contrast media were monitored over time during 2 hours in the double-contrast group (in vivo), using a microdialysis technique and analysed by inductively coupled plasma atomic emission spectrometry (ICP-AES). The infarctions demonstrated a high SI in the proton density- and T2-weighted sequences, in both the Dy-DTPA-BMA and control groups, although the former group demonstrated a 3-fold greater concentration of Dy in infarcted compared with non-ischaemic myocardium. Dy-DTPA-BMA did not counteract the Gd-DTPA-BMA-induced enhancement of the infarcted tissue despite a 3-fold higher concentration. This lack of detectable susceptibility effects of Dy may be caused by a loss of cell membrane integrity in the infarcts, resulting in a homogeneous intra- and extracellular distribution of the contrast agent. This hypothesis of an expanded volume of distribution in infarcted tissue was further supported by the microdialysis data, demonstrating a similar extracellular concentration of contrast agents in infarcted and non-ischaemic myocardium, despite a proven 3-fold greater concentration in infarcted tissue samples. To investigate whether Gd-DTPA-BMA-enhanced MR imaging (ex vivo) permits differentiation between reperfused and non-reperfused myocardial infarction, and whether Dy-DTPA-BMA-enhanced MR imaging enables a differentiation between reversible and irreversible myocardial injury following reperfusion, myocardial infarction was induced in 24 domestic pigs (divided into 4 groups) by placing a patched ligature around a diagonal branch of the LAD. Four additional hearts were reperfused after 2 min of brief occlusion, not long enough to cause irreversible injury.(ABSTRACT TRUNCATED AT 250 WORDS)

AUR Memorial Award. Identification of myocardial cell death in reperfused myocardial injury using dual mechanisms of contrast-enhanced magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Because the magnitude of dysprosium-induced signal loss depends on the microheterogeneity of its distribution (exclusion from intracellular space), we proposed that loss of myocardial cell integrity would be reflected by decreased potency of dysprosium in the injured compared with normal myocardium. We measured the effect of dysprosium on magnetic resonance (MR) imaging signal intensity of reperfused infarcted and nonischemic myocardium and related it to tissue concentration of the contrast media. METHODS: Rats were subjected to 1 hr coronary artery occlusion followed by 1 hr reperfusion. After 45 min of reflow, group 1 (n = 9) received 1.0 and 0.2 mmol/kg dysprosium diethylenetriamine pentaacetic acid-bismethylamide (Dy-DTPA-BMA) and gadodiamide (Gd-DTPA-BMA), respectively. Group 2 (n = 7) received no contrast agents. Excised hearts were imaged with spin-echo T1- and T2-weighted sequences. After imaging, hearts were stained (triphenyltetrazolium chloride) to define the injured zones. Concentrations of Dy-DTPA-BMA and Gd-DPTA-BMA in regional myocardial tissue were determined by induction coupled plasma-atomic emission spectrometry. Separate groups received one or the other contrast medium alone to control for potential error from the mixed effects of the two agents. RESULTS: Gd-DTPA-BMA delineated reperfused infarcted myocardium as a bright zone on T1-weighted images, thus indicating delivery of the agent and reperfusion at the tissue level. Dy-DTPA-BMA delineated the reperfused infarction as a bright region by decreasing the signal intensity of nonischemic myocardium significantly more than that of injured myocardium, despite being present in greater concentration (by 2.46-fold) in the injured myocardium. CONCLUSION: These findings are consistent with the hypothesis that the failure of myocardial cells to exclude the dysprosium compound is responsible for the diminished potency of dysprosium to cause MR imaging signal intensity loss in reperfused myocardial infarction. The combination of the two contrast media may define reperfusion of the myocardium at the tissue level (Gadolinium distribution) and the presence and extent of myocardial necrosis (diminished dysprosium effect) in reperfused myocardial infarctions.

A comparative study of the safety and efficacy of dysprosium-165 hydroxide macro-aggregate and yttrium-90 silicate colloid in radiation synovectomy--a multicentre double blind clinical trial. Australian Dysprosium Trial Group.

The aim of our study was to compare the safety and efficacy of a new preparation, Dysprosium-165 Hydroxide Macroaggregate (165Dy) with Yttrium-90 Silicate (90Y) for radiation synovectomy of the knee in patients with RA and OA. A multicentre double blind clinical trial with subjects randomized to receive 165Dy or 90Y was undertaken in Sydney, Melbourne and Perth. Seventy knees of 59 patients were studied, using as clinical end point measurements, pain in the knee on walking, pain in the knee at rest and stiffness in the knee after rest. Cytogenetic damage, knee retention and extra-articular spread of the radionuclide to regional lymph nodes, liver, urine and blood were evaluated. There was no significant difference in clinical response in the two treatment groups for either RA or OA. Chromosomal changes occurred with equal frequency and the knee retention and extra-articular leakage of radiocolloids to regional lymph nodes and liver were comparable in the two groups. For radiation synovectomy of the knee, 165Dy is at least as safe and as effective as 90Y and has the advantage of a short half-life (2.334 h) and hence requires a shorter period of post-injection immobilization and hospitalization.

[Radiosynovectomy with dysprosium-165 iron hydroxide]. / Radiosynovektomie mit Dysprosium-165-Eisen-Hydroxid.

Treatment of chronic rheumatoid synovitis (RS) is directed to control the inflammatory process causing pain and disability. Radiation synovectomy is suggested to be an alternative to surgical treatment, but its clinical use has been restricted because of significant leakage (> 10%) associated with the use of the standard radionuclide 90-Yttrium (used as 90-Yttrium silicate colloid) and because of its long physical half-life of 64 hours prolonging the patients' stay in the hospital. 165-Dysprosium possesses promising nuclear properties for the treatment of patients suffering from RS. The maximum soft tissue penetration of its beta-particles is 5.7 mm which is the range being necessary to penetrate the inflamed synovia. Using as carrier ferric hydroxide macroaggregates (DFH) 165-Dy is expected to minimize the cumulative radiation dose to non-target organs by its very low leakage. Animal studies were performed in 13 rats and 6 rabbits to obtain the rationale and safety data for its clinical evaluation. These studies revealed that 98.2 +/- 0.6% of the injected dose remained in the joint with a nontarget organ uptake of less than 0.1%. Clinical results were obtained from 8 patients with rheumatoid arthritis. 24 hours after injection scintigraphy was performed over the treated joint and the liver region revealing no detectable leakage of the injected activity from the joint. Blood pool activity was also assessed revealing a leakage of 0.02% of the dose injected in the knee 24 hours after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Dysprosium (165Dy) hydroxide macroaggregates for radiation synovectomy--animal studies.

This paper reports the development of a new chemical formulation, Dy-HMA, to utilise the advantages of dysprosium 165 in radiation synovectomy of certain forms of arthritis. Dy-HMA is a sterile suspension of dysprosium hydroxide macroaggregates (approximately 6 mg Dy/ml) in saline with the majority of particles in the 3-5 microns range. The absence of ferric hydroxide and a higher concentration of dysprosium in the formulation offer advantages over dysprosium ferric hydroxide macroaggregates, Dy-165-FHMA. Biodistribution studies in rats and rabbits with Dy-HMA show less leakage than with Dy-FHMA and considerably less leakage than with yttrium silicate colloid. Rabbits treated with intra-articular injections of Dy-HMA equivalent to 10-30 times the typical clinical dose showed no signs of any toxic effects.