Production and novel radiochemical separation of 194Au from Pt for use in multi-modality nanoparticles: Production and novel radiochemical separation of 194Au from Pt for use in multi-modality nanoparticles

Introduction Gold nanoparticles (AuNPs) have demonstrated their incredible versatility in applications such as in vitro and in vivo imaging, cancer therapy, and drug delivery.[1-3] These AuNPs come in many shapes including nanospheres, nanorods, nanoshells, and nanocages. Their versatility stems from the ability to construct or label a single AuNP with many functions. Many types of AuNPs are inherently flourescent, allowing for ex vivo utilization as well as small animal fluorescence imaging.[4] High atomic number and physical density allow for the possibility of using AuNPs as computed tomography (CT) contrast agents, especially in dual energy applications.[5] Some attempts have been made to bring AuNPs into the realm of nuclear medicine, mostly involving the extrinsic labeling of chelated radio-metals. Although these strategies have brought some success, an intrinsic labeling strategy could reduce concerns of in vivo instability, and changes in pharmacokinetic behavior.[6] Intrinsic radiolabeling strategies involve synthesizing the nanoparticles in the presence of a gold radioisotope, which is thereby structurally incorporated. The isotope of choice for this technique has typically been 198Au (t½ = 2.7 d, Eγ = 411.8 keV) as it is reactor produced and commercially available. However with such a high energy gamma ray, SPECT aquisition is far from optimal. Motivated by the shortcomings of previous intrinsic labeling techniques, we have sought to develop 194Au (t½ = 1.48 d, β+ = 1.73 %) as a potential PET isotope for labeling AuNPs. Although this nuclide has a weak positron branching ratio, it also has prominent gamma ray energies of 328 and 294 keV which are closer to the optimal SPECT energy window, allowing for the ability to image with both PET and SPECT. Material and Methods 194Au was produced by natPt(p,x) using 16 MeV protons. Target construction consisted of a water jet cooled platinum disc. Following irradiation, targets were etched by fresh concentrated aqua regia at 80 °C for four hours. The resulting solution was diluted by a factor of four and loaded onto a 50 mg UTEVA (Eichrom extraction resin) column equilibrated by 1 M HNO3. The column was rinsed with 10 mL 1 M HNO3, and the product was eluted using concentrated HNO3 in less than 1 mL. Results and Conclusion End of bombardment (EOB) yield for 194Au was measured to be 0.134 mCi/μAh by high purity germanium analysis. The half life was measured to be 38.5 ± 2.8 hours, which agrees well with the true half life of 37.92 hours. In addition to the production of 194Au, the production of 190–193Au and 196Au was observed. Most notably, the EOB yield for 193Au (t½ = 17.7 h) was 0.189 mCi/μAh. Target dissolution was slow and incomplete after four hours of etching. Alternative dissolution strategies i.e. electrolytic dissolution may be needed moving forward. The separation of 194Au from bulk Pt via the UTEVA extraction resin was robust and efficient, with an average separation efficiency of 96 %. An extensive literature review revealed no other Au/Pt separation from solutions containing aqua regia. Future goals include synthesis of ultrasmall 194Au incorporated AuNPs using a facile thermal reduction method.PET, CT and fluorescence imaging will also be carried out in vivo to establish the multimodal capabilities of the intrinsically radio-labeled nanoplatforms. To conclude, a novel separation technique has been developed to separate 194Au from Pt for use in intrinsically radiolabeled multi-modal AuNPs

Simplified targetry and separation chemistry for 68Ge production

Introduction 68Ge (t½ = 270.8 d, 100% EC) is an important radionuclide for two reasons: 1) once in equilib-rium with its daughter nuclide 68Ga (t½ = 68 min, 89 % β+, 3 % 1077 keV γ), it can be used as a positron source for attenuation correction and calibration of PET/MRI scanners; and 2) it can be employed as a generator of 68Ga for radiophar-maceutical preparation. Most isotope production facilities produce it using natural gallium (60.1% 69Ga, 39.9% 71Ga, melting point: 39 °C) as target material for proton bombardment at energies > 11.5 MeV, the threshold energy for 69Ga(p,2n)68Ge [1]. A maximum cross section of ~330 mb for natGa(p,x)68Ge occurs at ~20 MeV [1], hence proton energies in this neighborhood are mandatory for large scale production. Galli-um targetry is challenging due to its low melting point and corrosivity, hence compounds such as Ga2O3 (melting point: 1900 °C) or GaxNiy alloys (melting points > 800 °C) [2], have been used as target compounds [3,4,5]. The separation chem-istry technique employed by large-scale produc-tion facilities is liquid-liquid extraction using CCl4 [6,7]. In this work, two simple methods for GaxNiy alloy preparation are presented as well as a simple germanium separation procedure using a commercially available extraction resin. Material and Methods GaxNiy alloys were prepared by two methods (A,B). A) electrodeposition over 1.3 cm2 of a gold disk substrate. Ga2O3 and NiSO4.6H2O were dis-solved in a mixture of (27%) H2SO4 and NH4OH at pH 1.5 in a 3:2 mass ratio so that the Ga:Ni molar ratio was 4:1. The solution was then transferred to a 15 mL plating cell, in which a current of 29 mA/cm2 was applied with a platinum anode at 1 cm from the gold surface. B) Ga pellets were fused together with Ni powder at different Ga:Ni molar ratios using an induction furnace (EIA Power Cube 45/900). The resulting alloy pellets were then rolled to foils using a jeweler’s mill pressed between Nb foils to avoid contamination. Target irradiations were performed on a GE PETtrace at 16 MeV protons. The electroplated alloys were mounted on a custom-made solid target irradiation system with direct water-jet cooling applied to the backside of the gold disk. The alloy foils were placed on top of in a 1.2 cm diameter, 406 μm deep pocket made of Nb and sealed against a 51 μm Nb foil using a teflon O-ring. The alloys were in direct contact with the Nb foil to allow thermal conduction. At the rear of the Nb pocket is a water-cooling stream to transfer heat convectively during irradiation. Ge separation was achieved based on the difference in distribution coefficients between Ge, Ga, Zn, Cu, Ni and Co at different HNO3 molarities in DGA resin (Triskem International). Initial tests on the resin were performed after two pilot irradiations on natural gallium (a,b). a) 16 MeV protons were directed downward on an external beam-line (−30 °) onto 640 mg of molten elemental natGa pooled on a water-cooled niobium support. b) 330 mg natGa pellet was melted in the same Nb pocket well used with the alloys and was also sealed against a 51 μm Nb foil. The irradiated gallium was left to decay for 2 weeks and then was dissolved in 6 mL of concentrated HNO3. The solution was then passed through 200 mg of DGA resin packed in a 5 mm diameter column at a flow rate of 1.1 mL/min. A separation profile for Ge, Ga and Zn was obtained by collecting 0.2–1.0 mL fractions, which were analyzed by gamma ray spectroscopy on a HPGe detector. Two thick NiGa4 foils have been irradiated, one for 69Ge production and for radiocobalt, from 58Ni(p,α), separation quantification; and the other one for 68Ge production with the idea of preparing a mini-generator (< 13 MBq) of 68Ga for local use in phantom imaging work and animal studies. Results and Conclusion A) Each electroplating batch consisted of 66.5 ± 2.9 mg of Ga2O3 mixed with 44.9 ± 3.6 mg of NiSO4.6H2O (n = 9) in the 15 mL plating cell. Higher concentrations resulted in inefficient electroplating yields due to precipitation. 66 ± 6 % of the total Ga+Ni mass in solution, that is 39.5 ± 3.3 mg of Ga-Ni was deposited after 3 d. Three plating batches over one disk resulted in a maximum target thickness of 86.7 mg/cm2. A fourth batch did not add any significant amount of alloy and salt precipitation became a problem. The electroplated surface looked homogeneous at 10× magnification on a microscope and the targets were able to withstand up to 30 μA without presenting any dark spots. B) Alloys with Ga:Ni molar ratios of 1.0, 2.0, 2.9, 3.7 and 5.2 were fused by induction heating. TABLE 1 summarizes the results from manipulating these foils. These alloys were analyzed by X-ray fluorescence using a 109Cd excitation source quantifying the x-rays peaks: 9.26 keV for Ga and 7.48 keV for Ni. A linear relationship between the ratio of count rates of these two peaks to the alloy Ga:Ni molar ratio was found and employed for the characterization of the electroplated Ga-Ni layers. Results from the irradiations over natGa on Nb supports are presented in TABLE 2. TABLE 3 presents the results from irradiating two thick NiGa4 foils made by induction heating. Figure 1 contains the separation profile with DGA. 91% of the 68Ge is eluted in 2 mL of de-ionized water. We developed two simple methods for NiGa4 alloy manufacture. With a melting point > 800 °C and 80% presence of natGa, it is a more convenient target for 68Ge production compared to Ga encapsulated in Nb. The separation method based on the extraction resin DGA yields similar results as the liquid-liquid extraction method mentioned in [6,7], but we believe this is a more convenient method since it only requires a single trap-and-release step and not many extraction steps

Phylogeography of the Patagonian otter Lontra provocax: adaptive divergence to marine habitat or signature of southern glacial refugia?

<p>Abstract</p> <p>Background</p> <p>A number of studies have described the extension of ice cover in western Patagonia during the Last Glacial Maximum, providing evidence of a complete cover of terrestrial habitat from 41°S to 56°S and two main refugia, one in south-eastern Tierra del Fuego and the other north of the Chiloé Island. However, recent evidence of high genetic diversity in Patagonian river species suggests the existence of aquatic refugia in this region. Here, we further test this hypothesis based on phylogeographic inferences from a semi-aquatic species that is a top predator of river and marine fauna, the huillín or Southern river otter (<it>Lontra provocax</it>).</p> <p>Results</p> <p>We examined mtDNA sequences of the control region, ND5 and Cytochrome-b (2151 bp in total) in 75 samples of <it>L. provocax </it>from 21 locations in river and marine habitats. Phylogenetic analysis illustrates two main divergent clades for <it>L. provocax </it>in continental freshwater habitat. A highly diverse clade was represented by haplotypes from the marine habitat of the Southern Fjords and Channels (SFC) region (43°38' to 53°08'S), whereas only one of these haplotypes was paraphyletic and associated with northern river haplotypes.</p> <p>Conclusions</p> <p>Our data support the hypothesis of the persistence of <it>L. provocax </it>in western Patagonia, south of the ice sheet limit, during last glacial maximum (41°S latitude). This limit also corresponds to a strong environmental change, which might have spurred <it>L. provocax </it>differentiation between the two environments.</p

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems

New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous WIA in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little, while not much new information has been gathered on soil organisms. The impact on marine coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal classneonicotinoids and fipronil. , withContinued large scale – mostly prophylactic – use of these persistent organochlorine pesticides has the potential to greatly decreasecompletely eliminate populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates, and their deleterious impacts on growth, reproduction and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015)

Imidacloprid-Induced Impairment of Mushroom Bodies and Behavior of the Native Stingless Bee Melipona quadrifasciata anthidioides

Declines in pollinator colonies represent a worldwide concern. The widespread use of agricultural pesticides is recognized as a potential cause of these declines. Previous studies have examined the effects of neonicotinoid insecticides such as imidacloprid on pollinator colonies, but these investigations have mainly focused on adult honey bees. Native stingless bees (Hymenoptera: Apidae: Meliponinae) are key pollinators in neotropical areas and are threatened with extinction due to deforestation and pesticide use. Few studies have directly investigated the effects of pesticides on these pollinators. Furthermore, the existing impact studies did not address the issue of larval ingestion of contaminated pollen and nectar, which could potentially have dire consequences for the colony. Here, we assessed the effects of imidacloprid ingestion by stingless bee larvae on their survival, development, neuromorphology and adult walking behavior. Increasing doses of imidacloprid were added to the diet provided to individual worker larvae of the stingless bee Melipona quadrifasciata anthidioides throughout their development. Survival rates above 50% were only observed at insecticide doses lower than 0.0056 µg active ingredient (a.i.)/bee. No sublethal effect on body mass or developmental time was observed in the surviving insects, but the pesticide treatment negatively affected the development of mushroom bodies in the brain and impaired the walking behavior of newly emerged adult workers. Therefore, stingless bee larvae are particularly susceptible to imidacloprid, as it caused both high mortality and sublethal effects that impaired brain development and compromised mobility at the young adult stage. These findings demonstrate the lethal effects of imidacloprid on native stingless bees and provide evidence of novel serious sublethal effects that may compromise colony survival. The ecological and economic importance of neotropical stingless bees as pollinators, their susceptibility to insecticides and the vulnerability of their larvae to insecticide exposure emphasize the importance of studying these species

Baseline characteristics of patients in the reduction of events with darbepoetin alfa in heart failure trial (RED-HF)

&lt;p&gt;Aims: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.&lt;/p&gt; &lt;p&gt;Methods and results: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate &#60;60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.&lt;/p&gt; &lt;p&gt;Conclusion: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.&lt;/p&gt