Search Results (20)

The success of multiple nuclear medicine radiotherapeutics in treating cancer requires an increased supply of companion diagnostic imaging agents radiolabeled with gallium-68. Cyclotron production addresses the need for access to gallium-68 and has been validated for use with commercially produced sterile kits. For novel research tracers undergoing translational studies (IND or RDRC), developing and purchasing sterile kits is time- and cost-prohibitive. An on-cassette labeling method with terminal filtration allows non-sterile kits to be fabricated in-house, simplifying workflow and allowing multiple PET imaging agents to be evaluated using the same kit (i.e., parts, reagents, and timelist) with minimal variation. Using modified GE gallium chloride cassettes, four diverse clinically relevant tracers (DOTA-TOC, FAPI-04, pentixafor, and PSMA-11) were radiolabeled with gallium-68 to evaluate the approach using DOTA and HBED-CC chelator types. The tracers were all formulated according to established FDA-approved formulations and sterile-filtered using a PVDF membrane. The automated procedure is robust, tolerating DOTA and HBED-CC chelators, and can be used to screen numerous gallium-68 agents for rapid translation to clinical use. Full article

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100–1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as ⁶⁸Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., ¹⁷⁷Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma. Full article

Acidic amino acid peptides have a high affinity for bone. Previously, we demonstrated that radiogallium complex-conjugated oligo-acidic amino acids possess promising properties as bone-seeking radiopharmaceuticals. Here, to elucidate the effect of stereoisomers of Glu in Glu-containing peptides [(Glu)₁₄] on their accumulation in the kidney, the biodistributions of [⁶⁷Ga]Ga-N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid-conjugated (l-Glu)₁₄ ([⁶⁷Ga]Ga-HBED-CC-(l-Glu)₁₄), [⁶⁷Ga]Ga-HBED-CC-(d-Glu)₁₄, [⁶⁷Ga]Ga-HBED-CC-(dl-Glu)₁₄, and [⁶⁷Ga]Ga-HBED-CC-(d-Glu-l-Glu)₇ were compared. Although the accumulation of these compounds in the bone was comparable, their kidney accumulation and retention were strikingly different, with [⁶⁷Ga]Ga-HBED-CC-(d-Glu-l-Glu)₇ exhibiting the lowest level of kidney accumulation among these compounds. Repeated d- and l-peptides may be a useful method for reducing renal accumulation in some cases. Full article

The dynamic mechanisms and intramolecular isotope effects of the Be(¹S) + HD (v₀ = 2, j₀ = 0) → BeH/BeD + H/D reaction are studied at the state-to-state level using the time-dependent wave packet method on a high-quality potential energy surface. This reaction can proceed along the indirect pathway that features a barrier and a deep well or the smooth direct pathway. The reaction probabilities, total and state-resolved integral cross sections, and differential cross sections are analyzed in detail. The calculated dynamics results show that both of the products are mainly formed by the dissociation of a collinear HBeD intermediate when the collision energy is slightly larger than the threshold. As the collision energy increases, the BeH + D channel is dominated by the direct abstraction process, whereas the BeD + H channel mainly follows the complex-forming mechanism. Full article

In oligo-metastatic renal cell carcinoma (RCC), neither computed tomography (CT) nor bone scan is sensitive enough to detect small tumor deposits hampering early treatment and potential cure. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the neo-vasculature of numerous malignant neoplasms, including RCC, that can be targeted by positron emission tomography (PET) using PSMA-targeting radioligands. Our aim was to investigate whether PSMA-expression patterns of renal cancer in the primary tumor or metastatic lesions on immunohistochemistry (IHC) are associated with PET/CT findings using [⁶⁸Ga]-PSMA-HBED-CC (PSMA-PET/CT). We then analyzed the predictive and prognostic role of the PSMA-PET/CT signal. In this retrospective single-center study we included patients with renal cancer submitted to PSMA-PET/CT for staging or restaging, with tumor specimens available for PSMA-IHC. Clinical information (age, tumor type, and grade) and IHC results from the primary tumor or metastases were collected. The intensity of PSMA expression at IHC was scored into four categories: 0: none; 1: weak; 2: moderate; 3: strong. PSMA expression was also graded according to the proportion of vessels involved (PSMA%) into four categories: 0: none; 1: 1–25%; 2: 25–50%; 3: >50%. The intensity of PSMA expression and PSMA% were combined in a three-grade score: 0–2 absent or mildly positive, 3–4 moderately positive, and 5–6 strongly positive. PSMA scores were used for correlation with PSMA-PET/CT results. Results: IHC and PET scans were available for the analysis in 26 patients (22 ccRCC, 2 papillary RCC, 1 chromophobe, 1 “not otherwise specified” RCC). PSMA-PET/CT was positive in 17 (65%) and negative in 9 patients (35%). The mean and median SUVmax in the target lesion were 34.1 and 24.9, respectively. Reporter agreement was very high for both distant metastasis location and local recurrence (kappa 1, 100%). PSMA-PET detected more lesions than conventional imaging and revealed unknown metastases in 4 patients. Bone involvement, extension, and lesion number were greater than in the CT scan (median lesion number on PET/CT 3.5). The IHC PSMA score was concordant in primary tumors and metastases. All positive PSMA-PET/CT results (15/22 ccRCC, 1 papillary cancer type II, and 1 chromofobe type) were revealed in tumors with strong or moderate PSMA combined scores (3–4 and 5–6). In ccRCC tissue samples, PSMA expression was strong to moderate in 20/22 cases. The SUVmax values correlated to the intensity of PSMA expression which were assessed using IHC (p = 0.01), especially in the ccRCC subgroup (p = 0.009). Median survival was significantly higher in patients with negative PSMA-PET/CT (48 months) compared to patients with a positive scan (24 months, p= 0.001). SUVmax ≥ 7.4 provides discrimination of patients with a poor prognosis. Results of PSMA-PET/CT changed treatment planning. Conclusions: in renal cancer, positive PSMA-PET/CT is strongly correlated to the intensity of PSMA expression on immunohistochemistry in both ccRCC and chromophobe cancer. PSMA-PET/CT signal predicts a poor prognosis confirming its potential as an aggressiveness biomarker and providing paramount additional information influencing patient management. Full article

Cold plasma and ozone sanitation of irrigation solutions can oxidize both microbes and non-target micronutrients because their high oxidation-reduction potential (ORP) is a non-selective mode of action. The objective of this study was to evaluate the effects of cold plasma and ozone treatment on oxidation of iron and manganese in nutrient solutions containing one of four iron chelates (iron-ethylenediaminetetraacetic acid (Fe-EDTA), iron-diethylenetriaminepentaacetic acid (Fe-DTPA), iron-ethylenediamine-N,N′-bis(2-hydroxyphenylacetic acid) (Fe-EDDHA), and hydroxybenzyl ethylenediamine (Fe-HBED)). Nutrient solutions were recirculated through the cold plasma or ozone system until the ORP reached 700 mV. The concentrations of total dissolved iron, manganese, and chelated iron were measured before and after passing through the treatment systems. Both cold plasma and ozone oxidized chelates and decreased the solubility of iron and manganese. Cold plasma and ozone had similar effects on micronutrients, pH, electrical conductivity, and dissolved oxygen at a standardized target ORP of 700 mV. Fe-EDTA was the most resistant chelate to oxidation. With Fe-EDTA, ORP increased more quickly, and the concentration of chelated Fe decreased less with the increasing ORP over time compared with Fe-DTPA, Fe-EDDHA, and Fe-HBED. The concentration of chelated Fe decreased by up to 80% for EDDHA at 700 mV compared with a 20% decrease for EDTA. The concentration of Mn decreased by up to 85% at 700 mV. The design of water treatment with cold plasma or ozone therefore requires consideration of secondary effects on micronutrients. The treatment dosage, flow rate, and nutrient solution at a particular grower operation are likely to affect the quantity of micronutrient fertilizer that needs to be supplemented following treatment. Use of Fe-EDTA is one strategy to reduce the loss of iron and increase residual ORP that is available for sanitation. Full article

Positron emission tomography (PET) has been proven as an important technology to detect the expression of programmed death ligand 1 (PD-L1) non-invasively and in real time. As a PD-L1 inhibitor, small peptide WL12 has shown great potential in serving as a targeting molecule to guide PD-L1 blockade therapy in clinic. In this study, WL12 was modified with HBED-CC to label ⁶⁸Ga in a modified procedure, and the biologic properties were evaluated in vitro and in vivo. ⁶⁸Ga-HBED-CC-WL12 showed good stability in saline and can specifically target PD-L1-positive cells U87MG and PANC02. In PANC02-bearing mice, ⁶⁸Ga-HBED-CC-WL12 showed fast permeation in subcutaneous tumors within 20 min (SUV_max 0.37) and was of higher uptake in 90 min (SUV_max 0.38). When compared with 18F-FDG, ⁶⁸Ga-FAPI-04, and ⁶⁸Ga-RGD, ⁶⁸Ga-HBED-CC-WL12 also demonstrated great image quality and advantages in evaluating immune microenvironment. This study modified the ⁶⁸Ga-labeling procedure of WL12 and obtained better biologic properties and further manifested the clinical potential of ⁶⁸Ga-HBED-CC-WL12 for PET imaging and guiding for immunotherapy. Full article

The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The synthesis of radiochemically pure gallium-68 radiopharmaceuticals relies on careful consideration of the coordination chemistry. The short half-life of 68 min necessitates rapid quantitative radiolabelling (≤10 min). Desirable radiolabelling conditions include near-neutral pH, ambient temperatures, and low chelator concentrations to achieve the desired apparent molar activity. This review presents a broad overview of the requirements of an efficient bifunctional chelator in relation to the aqueous coordination chemistry of gallium. Developments in bifunctional chelator design and application are then presented and grouped according to eight categories of bifunctional chelator: the macrocyclic chelators DOTA and TACN; the acyclic HBED, pyridinecarboxylates, siderophores, tris(hydroxypyridinones), and DTPA; and the mesocyclic diazepines. Full article

Cellular iron supply is required for various biochemical processes. Measuring bioavailable iron in cells aids in obtaining a better understanding of its biochemical activities but is technically challenging. Existing techniques have several constraints that make precise localization difficult, and the lack of a functional readout makes it unclear whether the tested labile iron is available for metalloproteins. Here, we use geNOps; a ferrous iron-dependent genetically encoded fluorescent nitric oxide (NO) biosensor, to measure available iron in cellular locales. We exploited the nitrosylation-dependent fluorescence quenching of geNOps as a direct readout for cellular iron absorption, distribution, and availability. Our findings show that, in addition to ferrous iron salts, the complex of iron (III) with N,N’-bis (2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) can activate the iron (II)-dependent NO probe within intact cells. Cell treatment for only 20 min with iron sucrose was also sufficient to activate the biosensor in the cytosol and mitochondria significantly; however, ferric carboxymaltose failed to functionalize the probe, even after 2 h of cell treatment. Our findings show that the geNOps approach detects available iron (II) in cultured cells and can be applied to assay functional iron (II) at the (sub)cellular level. Full article

Iron (Fe) biofortification is a strategy to increase the amount of iron in food crops. The goal of this work was to assess the possibility of maximizing the Fe content in cherry tomatoes grown in a soilless system. The cultivar Creativo was grown with three concentrations of Fe (as Fe-HBED) in the nutrient solution (0.022, 1, and 2 mmol L⁻¹), and received further foliar applications of the element (as Fe-DTPA) at 0, 250, and 500 µmol L⁻¹. The addition of 2 mmol Fe L⁻¹ to the nutrient solution, together with foliar sprays at 500 µmol Fe L⁻¹, induced the highest increase in fruit Fe concentration in clusters 1 and 2 (by 163% and 190%, respectively). The Fe added to the nutrient solution increased the fruit dry matter (up to +10.21%) but decreased the fruit’s fresh weight (up to −11.06%). The higher Fe concentrations provided to the crop synergistically increased the contents of other minerals (i.e., K, Mg, Na, and Zn), along with the fruit’s titratable acidity and soluble solids content, improving multiple functional and quality traits of the cherry tomatoes. These results show that Fe biofortification of cherry tomatoes can be effective to address Fe deficiency while obtaining high-quality products. Full article

The present experiment addressed the effects of different iron (Fe) concentrations in the nutrient solution supplied as Fe-HBED, i.e., 0.02 (Fe0, control), 1.02 (Fe1), and 2.02 mmol L⁻¹ (Fe2) on lettuce (‘Nauplus’ and ‘Romana’) yield and compositional traits. This experiment was carried out in a greenhouse using an open soilless cultivation system, at the experimental farm of the University of Catania (Sicily, Italy: 37°24′31.5″ N, 15°03′32.8″ E, 6 m a.s.l.). The addition of Fe-HBED reduced the plants’ aboveground biomass (−18%, averaged over Fe1 and Fe2), but promoted their dry matter content (+16% in Fe2). The concentration of chlorophylls, carotenoids, anthocyanins, and antioxidants peaked at Fe2, along with the antioxidant capacity and concentration of stress indicators in leaves. The Fe content in leaves was promoted in the Fe-treated plants (+187% averaged over Fe1 and Fe2). ‘Romana’ showed the highest Fe accumulation (reaching 29.8 mg kg⁻¹ FW in Fe1), but ‘Nauplus’ proved a higher tolerance to the Fe-derived oxidative stress. The Fe2 treatment maximized leaf N, P, K, S, and Zn contents, while those of Ca, Mg, Mn, and B peaked at Fe1. Overall, our study revealed the effectiveness of Fe-HBED in increasing the Fe content and improving the nutritional quality of lettuce grown in soilless cultivation systems. Full article

The ever-increasing number of hospital Emergency Department (ED) visits pose a challenge to the effective running of health systems in many countries globally and multiple strategies have been adopted over the years to tackle the plight. According to a systematic review of the available literature, of the numerous models of healthcare systems used to address the issue in western countries, the FSED Model has the greatest potential for reducing hospital ED overcrowding as it can reduce the additional load by diverting minor cases, freeing up space for more urgent cases. The aim of the study is to shed light on the Free Standing Emergency Department (FSED) model and compare it with the traditional Hospital Based Emergency Department (HBED) in international contexts. In this study, 23 papers have been collected in a literature review and the main features have been highlighted; 12 case studies have been analyzed from a layout point of view and data have been collected in terms of surfaces, functions, and flow patterns. The percentages of floor areas devoted to each function have been compared to define evolution strategies in the development of emergency healthcare models and analyses. The use of FSED models is an interesting way to face the overcrowding problem and a specific range for functional area layout has been identified. Further studies on its application in different contexts are encouraged. Full article

Mushrooms fortified with iron (Fe) can offer a promising alternative to counter the worldwide deficiency problem. However, the factors that may influence the efficiency of fortification have not yet been fully investigated. The aim of this study was to compare the effects of three Fe forms (FeCl₃ 6H₂O, FeSO₄ 7H₂O, or FeHBED) in three concentrations (5, 10, or 50 mM) for three mushroom species (Pleurotus eryngii, P. ostreatus, or Pholiota nameko) on their chemical composition, phenolic compounds, and organic acid production. The most effective metal accumulation of all the investigated species was for the 50 mM addition. FeCl₃ 6H₂O was the most favorable additive for P. eryngii and P. nameko (up to 145 and 185% Fe more than in the control, respectively) and FeHBED for P. ostreatus (up to 108% Fe more than in control). Additionally, P. nameko showed the highest Fe accumulation among studied species (89.2 ± 7.51 mg kg⁻¹ DW). The creation of phenolic acids was generally inhibited by Fe salt supplementation. However, an increasing effect on phenolic acid concentration was observed for P. ostreatus cultivated at 5 mM FeCl₃ 6H₂O and for P. eryngii cultivated at 5 mM FeCl₃ 6H₂O and 5 mM FeSO₄ 7H₂O. In the case of organic acids, a similar situation was observed. For P. ostreatus, FeSO₄ 7H₂O and FeHBED salts increased the formation of the determined organic acids in fruiting bodies. P. eryngii and P. nameko were characterized by a much lower content of organic acids in the systems supplemented with Fe. Based on the obtained results, we recommend starting fortification by preliminarily indicating which form of the element is preferred for the species of interest for supplementation. It also seems that using an additive concentration of 50 mM or higher is most effective. Full article

The biochemical relapse of prostate cancer is diagnostically challenging but of high clinical impact for subsequent patient treatment. PET/CT with radiolabeled PSMA ligands outperforms conventional diagnostic methods in the detection of tumor recurrence. Several radiopharmaceuticals were and are available for use. The aim of this study was to investigate whether the routinely applied [⁶⁸Ga]Ga-PSMA ligands PSMA-617, -I&T and -11 (HBED-CC) differ in physiological and pathological distribution, or in tumor detection rate. A retrospective evaluation of 190 patients (39 patients received PSMA-617, 68 patients PSMA-I&T and 83 patients PSMA-11) showed significant differences in tracer accumulation within all organs examined. The low retention within the compartments blood pool, bone and muscle tissue is a theoretical advantage of PSMA-11. Evaluation of tumor lesion uptake and detection rate did not reveal superiority of one of the three radiopharmaceuticals, neither in the whole population, nor in particularly challenging subgroups like patients with very low PSA levels. We conclude that all three [⁶⁸Ga]Ga-PSMA ligands are equally feasible in this clinically important scenario, and may replace each other in case of unavailability or production restrictions. Full article

By using solid targets in medical cyclotrons, it is possible to produce large amounts of ⁶⁸GaCl₃. Purification of Ga³⁺ from metal ion impurities is a critical step, as these metals compete with Ga³⁺ in the complexation with different chelators, which negatively affects the radiolabeling yields. In this work, we significantly lowered the level of iron (Fe) impurities by adding ascorbate in the purification, and the resulting ⁶⁸GaCl₃could be utilized for high-yield radiolabeling of clinically relevant DOTA-based tracers. ⁶⁸GaCl₃ was cyclotron-produced and purified with ascorbate added in the wash solutions through the UTEVA resins. The ⁶⁸Ga eluate was analyzed for radionuclidic purity (RNP) by gamma spectroscopy, metal content by ICP-MS, and by titrations with the chelators DOTA, NOTA, and HBED. The ⁶⁸GaCl₃eluate was utilized for GMP-radiolabeling of the DOTA-based tracers DOTATOC and FAPI-46 using an automated synthesis module. DOTA chelator titrations gave an apparent molar activity (AMA) of 491 ± 204 GBq/µmol. GMP-compliant syntheses yielded up to 7 GBq/batch [⁶⁸Ga]Ga-DOTATOC and [⁶⁸Ga]Ga-FAPI-46 (radiochemical yield, RCY ~ 60%, corresponding to ten times higher compared to generator-based productions). Full quality control (QC) of ⁶⁸Ga-labelled tracers showed radiochemically pure and stable products at least four hours from end-of-synthesis. Full article