RESUMEN
Radionuclide production and development has a long history at the Paul Scherrer Institute (PSI) and dates back to the founding times of its forerunner institutions: the Federal Institute for Reactor Research and the Swiss Institute for Nuclear Research. The facilities used for this purpose have evolved substantially over the last five decades. Many radiometals in use today, as radiopharmaceuticals, are for the diagnosis and treatment of disease, with the most popular means of detection being Positron Emission Tomography. These positron emitters are easily produced at low proton energies using medical cyclotrons, however, developments at these facilities are lacking. Currently, the fixed 72 MeV proton beam at PSI is degraded at IP2 irradiation station to provide the desired energy to irradiate targets to produce the likes of 44Sc, 43Sc and 64Cu as a proof of principle, which are of great interest to the nuclear medicine community. This development work can then be implemented at facilities containing medical cyclotrons. A history of the development of radionuclides at PSI, along with current development and projects with partner institutions, is described.
RESUMEN
Terbium-149 (T1/2 = 4.1 h, Eα = 3.98 MeV (16.7%), 28 µm range in tissue) is a radionuclide with potential for targeted alpha therapy. Due to the negligible emission of α-emitting daughter nuclides, toxicity to healthy tissue may be reduced in comparison with other α-particle emitters. In this study, terbium-149 was produced via 1.4 GeV proton irradiation of a tantalum target at the CERN-ISOLDE facility. The spallation products were mass separated and implanted on zinc-coated foils and, later, radiochemically processed. Terbium-149 was separated from the co-produced isobaric radioisotopes and the zinc coating from the implantation foil, using cation-exchange and extraction chromatographic techniques, respectively. At the end of separation, up to 260 MBq terbium-149 were obtained with > 99% radionuclidic purity. Radiolabeling experiments were performed with DOTATATE, achieving 50 MBq/nmol apparent molar activity with radiochemical purity > 99%. The chemical purity was determined by inductively coupled plasma-mass spectrometry measurements, which showed lead, copper, iron and zinc only at ppb level. The radiolabeling of the somatostatin analogue DOTATATE with [149Tb]TbCl3 and the subsequent in vivo PET/CT scans conducted in xenografted mice, showing good tumor uptake, further demonstrated product quality and its ability to be used in a preclinical setting.
Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Mejoramiento de la Calidad , Terbio , Animales , Ratones , Radioisótopos/uso terapéutico , ZincRESUMEN
The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the ß+-emitter 68Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic ß--emitters 177Lu and 90Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68Ga is usually obtained via 68Ge/68Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68Ga-based diagnostic radiotracers. A promising solution is the production of 68Ga by means of proton irradiation of enriched 68Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68Ga, 67Ga and 66Ga production cross-sections using natural Zn and enriched 68Zn material, which served as the basis to perform optimized 68Ga production tests with enriched 68Zn solid targets.
Asunto(s)
Ciclotrones , Neoplasias de la Próstata , Radioisótopos de Galio/metabolismo , Humanos , Masculino , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Radioisótopos , Radiofármacos/metabolismoRESUMEN
BACKGROUND: Terbium-155 [T1/2 = 5.32 d, Eγ = 87 keV (32%) 105 keV (25%)] is an interesting radionuclide suitable for single photon emission computed tomography (SPECT) imaging with potential application in the diagnosis of oncological disease. It shows similar decay characteristics to the clinically established indium-111 and would be a useful substitute for the diagnosis and prospective dosimetry with biomolecules that are afterwards labeled with therapeutic radiolanthanides and pseudo-radiolanthanides, such as lutetium-177 and yttrium-90. Moreover, terbium-155 could form part of the perfect "matched pair" with the therapeutic radionuclide terbium-161, making the concept of true radiotheragnostics a reality. The aim of this study was the investigation of the production of terbium-155 via the 155Gd(p,n)155Tb and 156Gd(p,2n)155Tb nuclear reactions and its subsequent purification, in order to obtain a final product in quantity and quality sufficient for preclinical application. The 156Gd(p,2n)155Tb nuclear reaction was performed with 72 MeV protons (degraded to ~ 23 MeV), while the 155Gd(p,n)155Tb reaction was degraded further to ~ 10 MeV, as well as performed at an 18 MeV medical cyclotron, to demonstrate its feasibility of production. RESULT: The 156Gd(p,2n)155Tb nuclear reaction demonstrated higher production yields of up to 1.7 GBq, however, lower radionuclidic purity when compared to the final product (~ 200 MBq) of the 155Gd(p,n)155Tb nuclear reaction. In particular, other radioisotopes of terbium were produced as side products. The radiochemical purification of terbium-155 from the target material was developed to provide up to 1.0 GBq product in a small volume (~ 1 mL 0.05 M HCl), suitable for radiolabeling purposes. The high chemical purity of terbium-155 was proven by radiolabeling experiments at molar activities up to 100 MBq/nmol. SPECT/CT experiments were performed in tumor-bearing mice using [155Tb]Tb-DOTATOC. CONCLUSION: This study demonstrated two possible production routes for high activities of terbium-155 using a cyclotron, indicating that the radionuclide is more accessible than the exclusive mass-separated method previously demonstrated. The developed radiochemical purification of terbium-155 from the target material yielded [155Tb]TbCl3 in high chemical purity. As a result, initial cell uptake investigations, as well as SPECT/CT in vivo studies with [155Tb]Tb-DOTATOC, were successfully performed, indicating that the chemical separation produced a product with suitable quality for preclinical studies.
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The aim of this work was voltammetric determination of 1-aminopyrene and 1-hydroxypyrene using carbon paste electrodes modified with cyclodextrin derivatives and double stranded deoxyribonucleic acid (dsDNA). The detection schemes based on a preconcentration and differential pulse voltammetric (DPV) determination at beta-cyclodextrin and gamma-cyclodextrin modified carbon paste electrode (beta-CD/CPE, gamma-CD/CPE), neutral beta-cyclodextrin polymer and carboxymethyl-beta-cyclodextrin polymer modified screen-printed electrode (beta-CDP/SPE, beta-CDPA/SPE) and dsDNA modified screen-printed electrode (DNA/SPE) are proposed for the trace determination of studied analytes within the concentration range from 2 x 10(-8) to 4 x 10(-7) mol dm(-3) and from 2 x 10(-7) to 4 x 10(-6) mol dm(-3) with the limits of quantification down to 10(-8) mol dm(-3). Depending on pH, 1-aminopyrene interacts with both surface attached CD and DNA by electrostatic bonds and supramolecular complexation while 1-hydroxypyrene associates with the CD hosts via complexation. The 1-aminopyrene interaction with dsDNA was confirmed by fluorimetric measurements in the solution phase using a competing DNA-TO-PRO-3 dye complex. In addition, the effect of temperature on this association was investigated using an electrically heated DNA-modified carbon paste electrode (DNA/CPE).
Asunto(s)
Técnicas Biosensibles/métodos , Ciclodextrinas/química , ADN/química , Electroquímica/métodos , Pirenos/análisis , Carbono/química , Electrodos , PotenciometríaRESUMEN
Anodic-stripping voltammetry is used to perform automatic complexometric titrations of metal ions, with high precision. The stripping peaks are converted into corresponding titrant volume increments which are added consecutively during stripping. In analysis of samples containing about 1 mmole, each of lead, indium and gallium, relative standard deviations of 0.008-0.03% were attained.
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Hypochlorite was determined by direct coulometric titration with iron(II) in an acetate buffered solution. Chlorate was titrated with titanium(III) in 2M hydrochloric acid. Amperometric indication with one and two electrodes, respectively, was used. Mixtures of hypochlorites and chlorates, e.g., in industrial electrolytes, may be analysed. On a déterminé l'hypochlorite par titrage coulométrique direct avec le fer(II) dans une solution tamponnée à l'acétate. On a titré le chlorate avec le titane(III) en acide chlorhydrique 2M. On a utilisé l'indication ampérométrique une et deux électrodes respectivement. On peut analyser des mélanges d'hypochlorites et de chlorates, par exemple dans des électrolytes industriels.
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From the precipitation borderlines in the pBi'-pH diagram, determined experimentally under CO(2)-free conditions, the stability constants of bismuth hydroxide, bismuthoxynitrate and bismuthoxyperchlorate have been established. The following values have been found Nitrate-medium: Perchlorate-medium: log *K(SO)(OH) = 5.2, log *K(SO)(OH) = 5.2; log *K(SO)(NO(3)) = -1.2, log*K(SO)(ClO(4)) = -0.9; log *beta(2) = -4.0, log *beta(2) = -4.1; log *beta(3) = -10.0, log *beta(3)= -9.9; log *beta(4) = -21.5, log *beta(4) = -21.5; log *beta(1,0,1) = 1.2, log *beta(1,0,1) = 3.5. The constants refer to precipitates equilibrated for 30 min, prepared at room temperature (23 +/- 0.5 degrees) in sodium perchlorate or sodium nitrate medium with an ionic strength of 1.00 +/- 0.01. Concerning error propagation it is stated that pBi' values calculated with these constants will have a standard deviation of about 0.1 log unit.
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The structural changes in cytochrome c with temperature have been been followed using a recently developed electrically-heated microelectrode sensor. Differential pulse voltammetry was used to perform electrochemical measurements of cytochrome c oxidation at different temperatures at heated bare gold electrodes contained in phosphate-buffered cytochrome c solution at room temperature. The voltammetric response shows the onset of unfolding and a marked dependence of the signal on electrode temperature. This augurs well for applications of heated electrodes as local probes in the study of the temperature dependence of electron transfer processes of other redox proteins, avoiding problems of bulk deterioration.
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Grupo Citocromo c/química , Animales , Técnicas Biosensibles , Electroquímica , Oro , Caballos , Calor , Hierro/química , Microelectrodos , Oxidación-Reducción , Desnaturalización Proteica , Pliegue de Proteína , Propiedades de SuperficieRESUMEN
An overview is given describing phenomena at heated microelectrodes where matter and heat energy are simultaneously emitted into the solution. With controlled electric heating, virtual "quiescent" periods as well as ones with constant streaming conditions are found that depend on the heating time. A close look at a permanently heated wire reveals a well defined structure with stationary concentration, temperature and flow rate profiles. The observed phenomena can be utilised for analytical measurements, e.g. with the novel method "Temperature Pulse Voltammetry" (TPV).
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Microelectrodos , Temperatura , Termodinámica , ADN/química , Oxidación-Reducción , Factores de TiempoRESUMEN
A new electrochemical technique is presented that allows peak-shaped voltammograms to be recorded at local temperature values from room temperature to above boiling point. This new method, temperature pulse voltammetry (TPV), is analogous to differential pulse voltammetry (DPV), but makes use of temperature jumps instead of potential pulses. Fundamentals are presented and potentialities demonstrated. As an example, ferrocyanide is investigated using a new kind of heated electrode on the basis of screen-printed gold layer structures on low-temperature cofired ceramics (LTCC) substrates.
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A 27-year-old man with type F botulism (classification undetermined) had two episodes of botulinum toxaemia with identification of botulinum toxin and Clostridium botulinum organisms in faecal specimens during a three-month stay in hospital. Between these clinical episodes neither toxin nor Cl botulinum could be demonstrated. The illness was severe with quadriplegia, respiratory insufficiency, and bowel paralysis. In addition the patient had sensory abnormalities and a raised protein in the cerebrospinal fluid. The results demonstrate for the first time in detail an intestinal colonisation with and multiplication of C botulinum organisms and in-vivo production of toxin in an adult. The clinical findings at first pointed to Guillain-Barré syndrome, and it is suggested that patients with this syndrome should be examined for botulinum toxin in serum and for toxin and organisms in stool.
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Toxinas Botulínicas/sangre , Botulismo/diagnóstico , Clostridium botulinum/aislamiento & purificación , Enfermedades Intestinales/diagnóstico , Adulto , Clostridium botulinum/clasificación , Diagnóstico Diferencial , Humanos , Masculino , Polirradiculoneuropatía/diagnósticoRESUMEN
This paper describes the design of a hot-wire electrochemical flow detector, and the advantages accrued from the effects of locally increased temperature, mainly thermally induced convection, upon the amperometric monitoring of flowing streams. A new hydrodynamic modulation voltammetric approach is presented, in which the solution flow rate remains constant while the temperature of the working electrode is modulated. Factors influencing the response, including the flow rate, temperature pulse, or applied potential, have been investigated. The hot-wire operation results also in a significant enhancement of the flow injection amperometric response. The minimal flow rate dependence observed with the heated electrode should benefit the on-line monitoring of streams with fluctuated natural convection, as well as various in-situ remote sensing applications.
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Use has been made of a monoclonal antibody (designated 8F5) to map a neutralizing epitope on the viral capsid protein VP2 of human rhinovirus 2 (HRV2). This antibody which was raised against the native virus, neutralizes HRV2 and is also capable of recognizing denatured VP2 on Western blots. To examine the binding site of 8F5, VP2 of HRV2 was expressed in Escherichia coli. Deletions starting at the 3' end were then introduced into the gene for VP2 using Bal-31 nuclease. Polypeptides shortened at the carboxy terminus of VP2 were obtained from the deletions and were blotted onto nitrocellulose. The samples were then probed with monoclonal antibody 8F5. Recognition by 8F5 was maintained as long as the expressed polypeptide contained the VP2 sequence up to amino acid 164 or beyond. However, when the VP2 sequence was truncated to amino acid 153 or less 8F5 was no longer able to bind. The neutralization epitope (or part of it) recognized by 8F5 on VP2 is therefore located between amino acids 153 and 164.
Asunto(s)
Epítopos/inmunología , Rhinovirus/inmunología , Proteínas Virales/inmunología , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Sitios de Unión , Pruebas de Neutralización , Proteínas Recombinantes de Fusión/inmunología , Rhinovirus/clasificación , Proteínas Estructurales ViralesRESUMEN
A new electrically heated carbon paste electrode has been developed for performing adsorptive stripping measurements of trace nucleic acids. Such coupling of electrochemistry at electrically heated electrodes with adsorptive constant-current stripping chronopotentiometry offers distinct advantages for trace measurements of nucleic acids. The application of increased temperatures during the deposition step results in dramatic (4-34-fold, depending on temperature applied) enhancement of the stripping signal. Such improvement is attributed to the accumulation step at the heated electrode. Forced thermal convection near the electrode surface facilitates the use of quiescent solutions and hence of ultrasmall volumes. Using an electrode temperature of 32 degrees C and a quiescent solution during the 1-min accumulation, the response is linear over the 1-8 mg/L range tested, with a detection limit of 0.5 mg/L. Such electrode heating technology offers great promise for various applications involving thermal manipulations of nucleic acids.