Synthesis and functionalization of persistent luminescence nanoparticles with small molecules and evaluation of their targeting ability.

We have recently reported the design and use of inorganic nanoparticles with persistent luminescence properties. Such nanoparticles can be excited with a UV lamp for 2min and emit light in the near-infrared area for dozen of minutes without any further excitation. This property is of particular interest for small animal optical imaging, since it avoids the autofluorescence of endogenous fluorophores which is one major problem encountered when using fluorescent probes. We report herein the synthesis of persistent luminescence nanoparticles (PLNPs) and their functionalization with two small targeting molecules: biotin and Rak-2. We provide characterization of each PLNP as well as preliminary evidence of the ability of PLNP-PEG-Biotin to target streptavidin and PLNP-PEG-Rak-2 to bind prostate cancer cells in vitro.

Preparation of microcapsules containing rare-earth metal elements.

Microcapsules for internal radiation therapies containing the rare-earth metal elements Dy, Ho and Cu with a diameter of 5-10 microm were successfully obtained by an interfacial polymerization method and a successive sedimentation technique was employed to fractionate the microcapsules. A triisocyanate monomer and tricresylphosphate were used for a wall forming material and a core solvent for the metals, respectively. The amount of the metal elements loaded was measured using a high frequency plasma photoemission apparatus. The beta-ray radioactivity of 1 mg of microcapsules irradiated with a common neutron source is estimated as 370 microCi, which is satisfactorily strong for usual radiotherapy, when microcapsules containing Dy are used. Differential interference microscopy indicated narrow size distribution of the fractionated microcapulses.

Imaging perfusion deficits in ischemic heart disease with susceptibility-enhanced T2-weighted MRI: preliminary human studies.

AIM: This feasibility study explores relative myocardial perfusion characterization with an investigational T2/T2 contrast agent. METHODS: Dysprosium-DTPA bis (methylamide) was administered peripherally in six patients with thallium defects. Rest and stress multi-section, gated, T2-weighted images were acquired with a 1.5 T echo-planar imager. Change in transverse relaxation rate was calculated in four segments for each subject. RESULTS: Magnetic resonance (MR) identified five of five instances of ischemia or infarction, at a dose of agent (0.25 mmol/kg) that was comparable to that currently used with clinically approved gadolinium agents. Injection at twice this dose resulted in saturation of the signal change, and the one ischemic segment corresponding to the higher dose was not identified by MR. MR was negative in two segments which, on final diagnosis, were determined to manifest thallium attenuation artifact. CONCLUSION: MR perfusion imaging with high susceptibility agents has the potential to characterize myocardial perfusion deficits.

Delineation of liver necrosis using double contrast-enhanced MRI.

The purpose of this study was to demonstrate the potential usefulness of the combination of gadolinium and dysprosium to enhance the different between normal and necrotic liver tissue. Small regions of acute necrosis were induced by injecting 200-300 microliters of 95% alcohol into the liver of 26 rats. MRI was performed 24 hours after necrosis induction, before and immediately after injection of one or both contrast agents. Using a mixed T1/T2-weighted sequence, the signal intensity of (SI) of the normal liver was reduced by 70%, whereas the necrotic regions had more than a 50% increase in SI after double contrast. The region that was enhanced corresponded largely with the region of necrosis as observed postmortem. The lesion size, when identified, was largely underestimated using either of the agents along, albeit using the common pulse sequences. The double contrast effect of simultaneous administration of gadolinium and dysprosium allows accurate delineation of liver necrosis.

Combined perfusion and diffusion-weighted magnetic resonance imaging in a rat model of reversible middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging and dynamic first-pass bolus tracking of susceptibility contrast agents (perfusion imaging) are two new magnetic resonance imaging techniques that offer the possibility of early diagnosis of stroke. The present study was performed to evaluate the diagnostic information derived from these two methods in a rat model of temporary focal ischemia. METHODS: Fifteen male Wistar rats were assigned to 45 (n = 7) or 120 minutes (n = 8) of middle cerebral artery occlusion followed by reperfusion using the intraluminal filament technique. The diffusion-weighted images were collected, and areas of hyperintensity were compared with histologically assessed areas of ischemic injury. The magnetic resonance perfusion image series were postprocessed to produce topographic maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect. RESULTS: Hyperintensity in diffusion-weighted images was demonstrated after 30 minutes of middle cerebral artery occlusion and was mainly expressed in the lateral caudoputamen and parts of the lower frontoparietal cortex. Reperfusion after 45 minutes of occlusion reduced the area of hyperintensity from 24.2% to 9.9% of hemispheric area. In the group with 120 minutes of occlusion, the hyperintense area increased from 24.4% to 29.1%. Relative to the nonischemic hemisphere, the changes in the topographic maps of maximum signal reduction occurred in the lateral caudoputamen and adjacent lower neocortical areas. Increased time delay to maximum effect, however, was seen also in the upper frontoparietal cortex. CONCLUSIONS: Hyperintensity in diffusion-weighted images was reversible after 45 minutes but not after 120 minutes of middle cerebral artery occlusion. Analysis of the signal-reduction and time-delay parametric maps demonstrated regions of different perfusion changes in the ischemic hemisphere.

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.

MR imaging of cerebral perfusion by phase-angle reconstruction of bolus paramagnetic-induced frequency shifts.

Phase-angle images are acquired dynamically during bolus paramagnetic contrast injection and demonstrate a phase-enhancement effect in perfused cerebral tissues. Signal-to-noise is comparable to that of susceptibility-based signal loss (delta R*) images. Assuming that phase shift is proportional to the tissue paramagnetic agent concentration, as supported by experimental data, the integrated area of the phase time response curves estimated the relative gray to white matter blood volume as 1.8:1 and was sensitive to acute ischemia. The relation between tissue phase shift and concentration is considered.

Treatment of antigen-induced arthritis in rabbits with dysprosium-165-ferric hydroxide macroaggregates.

Dysprosium-165-ferric hydroxide macroaggregates (165Dy-FHMA) was used as an agent of radiation synovectomy in an antigen-induced arthritis model in New Zealand white rabbits. Animals were killed up to 6 months after treatment. 165Dy-FHMA was found to have a potent but temporary antiinflammatory effect on synovium for up to 3 months after treatment. Treated knees also showed significant preservation of articular cartilage architecture and proteoglycan content compared with untreated controls, but only during the first 3 months after treatment. In animals killed 3 and 6 months after treatment there were only minimal differences between the treated and untreated knees, indicating that the antiinflammatory effects on synovial tissue and articular cartilage preservation were not sustained.

Repeat radiation synovectomy with dysprosium 165-ferric hydroxide macroaggregates in rheumatoid knees unresponsive to initial injection.

Because of failure to fully respond to an initial intraarticular injection of dysprosium 165-ferric hydroxide macroaggregates, 17 patients with seropositive rheumatoid arthritis underwent repeat radiation synovectomy using this agent. Of the 13 patients who were evaluated 1 year later, 54% (7 knees) had good results, 31% (4 knees) had fair results, and 15% (2 knees) had poor results. The initial lack of significant benefit from radiation synovectomy did not appear to preclude a favorable response to a second injection.

Treatment of rheumatoid synovitis of the knee with intraarticular injection of dysprosium 165-ferric hydroxide macroaggregates.

One hundred eight knees of 93 patients with seropositive rheumatoid arthritis and persistent synovitis of the knee were treated with an intraarticular injection of 270 mCi of dysprosium 165 bound to ferric hydroxide macroaggregate. Leakage of radioactivity from the injected joint was minimal. Mean leakage to the venous blood 3 hours after injection was 0.11% of the injected dose; this corresponds to a mean whole body dose of 0.2 rads. Mean leakage to the liver 24 hours after injection was 0.64% of the injected dose; this corresponds to a mean liver dose of 3.2 rads. In 7 additional patients examined, there was negligible or near negligible activity found in the draining inguinal lymph nodes. One-year followup was possible for 74 knees (63 patients). Sixty-one percent of the knees had good results, 23% had fair results, and 16% had poor results. There was a direct correlation between the radiographic stage and response to treatment. In knees with stage I radiographic changes, 72% showed good results; 93% showed improvement. In knees with stage II changes, 59% showed good results; 81% showed improvement. These preliminary results indicate that dysprosium 165-ferric hydroxide macroaggregate is an effective agent for radiation synovectomy. The low leakage rates observed offer a definite advantage over agents previously used.

Intra-articular radiation synovectomy.

Fifty-three knees in 44 patients with severe, chronic rheumatoid arthritis (RA) were treated by the instillation of an intra-articular radionuclide (dysprosium-165; 165Dy) coupled with a large, relatively inert carrier (ferric hydroxide macroaggregate). The extremely low leakage rates found in earlier animal experiments were confirmed in the human, with a mean leakage rate of 0.3% of the injected dose. This leakage corresponds to a total body dose of 0.4 rad and a liver dose of 2.5 rad, equivalent to a lumbosacral series of diagnostic radiographs. Eighty percent of the treated knees showed improvement, which was maintained as long as one year after treatment. There was a direct correlation between the preoperative radiographic stage and the response to treatment, with patients in Stages I and II more likely to have a good or excellent response at one year. There was also good correlation between clinical improvement and improvement in technetium-99m (99mTc)-pertechnetate flow scintigraphy. Chemical synovectomy by the instillation of appropriate radionuclides can be recommended as an effective means of reducing inflammation, effusion, and pain in patients with RA. The duration of favorable results cannot be predicted, but the results to date suggest that longevity should be comparable with that of surgical synovectomy. Like surgical synovectomy, radiation synovectomy is most effective in the early stages of the disease process, before there is extensive destruction of cartilage and bone.

[Use of dysprosium considered as an activable tracer in the study of tooth structures]. / Utilisation du dysprosium en tant que traceur activable dans l'étude des structures dentaires.

After 32 days of administration to rats of dysprosium in drinking water, this element has been studied by neutron activation analysis in the intra-oral part of the incisors as well as in the molar crowns. This element was absent in the intra-osseous parts of the incisors, the femurs and the liver. After intravenous injection of 13 mg or 26 mg of Dy in several doses over 32 days, this element was found in the incisor formation and maturation zones as well as in the part having erupted in the oral cavity. It was also found in the molars, the femurs and the liver. The structural study has shown that no cytotoxic effect was observed with the dysprosium doses used. Dentinogenesis and amelogenesis were not disturbed. The final structures were homogeneous. By comparing the two administration ways of dysprosium we have at our disposal a study model using an inducible tracer of the incorporation of adsorption of a mineral element in dental structures during early or late maturations.