Ge Breakthrough Research Articles

Comprehensive Quality Control of the ITG 68Ge/68Ga Generator and Synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for Clinical Imaging.

A good-manufacturing-practices (GMP) (68)Ge/(68)Ga generator that uses modified dodecyl-3,4,5-trihydroxybenzoate hydrophobically bound to a octadecyl silica resin (C-18) as an adsorbent has been developed that allows for dilute HCl (0.05N) to efficiently elute metal-impurity-free (68)Ga(3+) ready for peptide labeling. We characterized the performance of this generator system over a year in conjunction with the production of (68)Ga-labeled DOTATOC and Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-HBED-CC) intended for clinical studies and established protocols for batch release. A 2,040-MBq self-shielded (68)Ge/(68)Ga generator provided metal-free (68)GaCl3 ready for peptide labeling in the fluidic labeling module after elution with 4 mL of 0.05N HCl. The compact system was readily housed in a laminar flow cabinet allowing an ISO class-5 environment. (68)Ga labeling of peptides using GMP kits was performed in 15-20 min, and the total production time was 45-50 min. Batch release quality control specifications were established to meet investigational new drug submission and institutional review board approval standards. Over a period of 12 mo, (68)Ga elution yields from the generator averaged 80% (range, 72.0%-95.1%), and (68)Ge breakthrough was less than 0.006%, initially decreasing with time to 0.001% (expressed as percentage of (68)Ge activity present in the generator at the time of elution), a unique characteristic of this generator. The radiochemical purity of both (68)Ga-DOTATOC and (68)Ga-PSMA-HBED-CC determined by high-performance liquid chromatography analysis was greater than 98%, with a minimum specific activity of 12.6 and 42 GBq/μmol, respectively. The radionuclidic ((68)Ge) impurity was 0.00001% or less (under the detection limit). Final sterile, pyrogen-free formulation was provided in physiologic saline with 5%-7% ethanol. The GMP-certified (68)Ge/(68)Ga generator system was studied for a year. The generator system is contained within the fluidic labeling module, and it is compact, self-shielded, and easy to operate using simple manual techniques. The system provides radiolabeled peptides with high (>98%) radiochemical purity and greater than 80% radiochemical yield. The (68)Ge levels in the final drug products were under the detection limits at all times. (68)Ga-DOTATOC and (68)Ga-PSMA-HBED-CC investigational radiopharmaceuticals are currently being studied clinically under investigational new drug (IND) applications submitted to the U.S. Food and Drug Administration.

A new (68)Ga anionic concentration and purification method for automated synthesis of [(68)Ga]-DOTA or NODAGA conjugated peptides in high radiochemical purity.

The (68)Ge/(68)Ga generator is of increasing interest for clinical PET. For successful labelling, the eluate has to be purified. The aim of our approach is to improve the existing anionic methods which have a number of advantages compared to other methods but which use high concentrated HCl, and require an additional anionizing step. A new (68)Ga-eluate anionic purification method that enables rapid and high efficiency labelling of DOTA and NODAGA conjugated peptides in high radiochemical purity is described. The new method uses NaCl as an alternative Cl(-) source to the corrosive HCl and combines the three standard steps in a single step. The recovery yield was ≥90%, and the (68)Ge breakthrough was in conformity with the European Pharmacopeia limit. An automated labelling of DOTA and NODAGA-conjugated peptides was performed with the new method, using acetate sodium buffer, with a total duration of 13 min and a radiochemical yield >85%. The labelled peptides have a radiochemical purity exceeding 99% and can be used directly without any further purification step and without the quality control by gas chromatography. Furthermore, the new method has an economic advantage: it offers the possibility to use generator until 20 months after the calibration date.

Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68)Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy.

BackgroundWith the increasing utilization of 68Ge-68Ga radionuclide generators, 68Ga labelled peptides like DOTATATE are receiving more attention in nuclear medicine. On the one hand, the long half-life of the parent nuclide 68Ge is an enormous advantage for routine applications, but the question of the long-term stability of the 68Ge breakthrough arises, which up to now has scarcely been investigated.MethodA sum of 123 eluates from four different 68Ge-68Ga generators (iThemba Labs, Faure, South Africa) and 115 samples of the prepared radiopharmaceutical 68Ga-DOTATATE were measured first with a dose calibrator and again after decay of the eluted 68Ga via gamma-ray spectrometry. A complete decay curve was recorded for one sample eluate. A further three eluates were eluted in ten fractions of 0.5 ml in order to obtain detailed information concerning the distribution of the two nuclides within the eluates. The influences of factors such as the amount of DOTATATE, addition of Fe3+ salts and replacement of HEPES buffer with sodium acetate on the radiochemical synthesis were also tested.ResultsThe content of long-lived 68Ge breakthrough increases over the entire period of use to more than 100 ppm. The labelling process with the chelator DOTA removes 68Ge efficiently. The maximum activity found in the residues of the radiopharmaceuticals investigated in this study was below 10 Bq in nearly all cases. In many cases (12% of the labelled substance), the long-lived parent nuclide could not be identified at all. The labelling process is still viable for reduced amounts of the chelator and with acetate buffer.ConclusionEffective doses received by the patient from 68Ge in the injected radiopharmaceutical 68Ga-DOTATATE are lower than 0.1 μSv and are therefore practically negligible, especially when compared with the contribution of the PET radiopharmaceutical itself. Gamma-ray spectrometry as recommended by the European Pharmacopeia is suitable for quantification of radionuclidic impurities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0036-4) contains supplementary material, which is available to authorized users.

Long-Term Evaluation of ‘BARC68Ge/68Ga Generator’ Based on the Nanoceria-Polyacrylonitrile Composite Sorbent

This article describes the long-term evaluation of a nanoceria-polyacrylonitrile (CeO2-PAN) composite sorbent-based (68)Ge/(68)Ga generator reported. This generator used the new CeO2-PAN composite sorbent for preparation of the (68)Ge/(68)Ga generator. Since this sorbent has not been previously evaluated, a thorough long-term evaluation of the performance of the generator is necessary to ensure its applicability for clinical practice. The performance of the generator was evaluated in terms of (68)Ga yield, (68)Ge breakthrough, radioactive concentration of the (68)Ga solution, and suitability of the (68)Ga for the preparation of (68)Ga-labeled tracers. The (68)Ge/(68)Ga generator was able to provide a (68)Ga activity with consistent yields (>70%) and having acceptable radionuclidic (<10(-4)% of (68)Ge breakthrough), radiochemical, and chemical purities for an extended period of time. The eluted (68)GaCl3 is useful for the majority of the (68)Ga complexation chemistry.

Optimization of Hapten-Peptide Labeling for Pretargeted ImmunoPET of Bispecific Antibody Using Generator-Produced 68Ga

Bispecific antibody pretargeting is highly sensitive and specific for cancer detection by PET. In this study, the preparation of a high-specific-activity (68)Ga-labeled hapten-peptide, IMP288, was evaluated. IMP288 (DOTA-D-Tyr-D-Lys(histamine-succinyl-glycine [HSG])-D-glu-D-Lys(HSG)-NH(2)) was added to buffered (68)Ga and then heated in boiling water and purified on a reversed-phase cartridge. Tumor-bearing nude mice were used for biodistribution and tumor localization studies. (68)Ga-IMP288 was prepared at a starting specific activity up to 1.78 GBq/nmol, with final yields of 0.74 GBq/nmol (decay-corrected) and less than 1% unbound (68)Ga. Purification was essential to remove unbound (68)Ga and (68)Ge breakthrough. Pretargeted animals showed a high (68)Ga-IMP288 uptake (27.5 ± 5.8 percentage injected dose per gram), with ratios of 13.6 ± 4.8, 66.8 ± 14.5, and 325.9 ± 61.9 for the kidneys, liver, and blood, respectively, at 1.5 h after peptide injection. High-specific-activity labeling of DOTA-hapten-peptide was obtained from the (68)Ga/(68)Ge generator for approximately 1 y, yielding products suitable for immunoPET.

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A fully automated synthesis for the preparation of 68Ga-labelled peptides

Generator-produced Ga has attracted increasing interest for radiolabelling peptides used in PET applications. So far, the synthesis of Ga-peptide radiopharmaceuticals is mainly based on semi-automated systems. Here we describe a fully automated approach for the synthesis of Ga-labelled peptides. A commercially available Ga generator was eluted with 0.1 mol . l HCl. Reaction parameters such as buffer conditions, pH range, reaction temperature and time, volume of reaction solution and generator fraction were optimized for labelling DOTA-Tyr-octreotide (DOTATOC). Reaction yields, pH, radiochemical purity, sterility, endotoxins, breakthrough of Ge and final Ge content were determined. A fully automated radiopharmaceutical synthesis device based on a modular concept for remote-controlled processing was developed and evaluated for a number of DOTA-derivatized peptides. DOTATOC could be labelled in almost quantitative yields by heating 10-50 nmol peptide at pH 3.5-4.0 for 5 min at 95 degrees C in 1.5 ml. Purification using a reversed-phase cartridge was required to avoid any potential Ge breakthrough: final activities of Ge were below 100 Bq . ml. Automated synthesis resulted in overall decay-corrected reaction yields of about 60% within 10 min. Even after 1 year using a 1110 MBq generator more than 130 MBq Ga-DOTATOC could be obtained. Moreover, it was demonstrated that a variety of DOTA-derivatized peptides can be labelled using identical reaction conditions with high yields. The system described allows the fully automated, efficient and rapid preparation of Ga-DOTA-derivatized peptides. It has been used successfully and reliably for routine preparations in clinical studies.

Suppression of Ge–O and Ge–N bonding at Ge–HfO 2 and Ge–TiO 2 interfaces by deposition onto plasma-nitrided passivated Ge substrates: Integration issues Ge gate stacks into advanced devices

A study of changes in nano-scale morphology of thin films of nano-crystalline transition metal (TM) elemental oxides, HfO 2 and TiO 2, on plasma-nitrided Ge(1 0 0) substrates, and Si(1 0 0) substrates with ultra-thin (∼0.8 nm) plasma-nitrided Si suboxide, SiO x , x < 2, or SiON interfacial layers is presented. Near edge X-ray absorption spectroscopy (NEXAS) has been used to determine nano-scale morphology of these films by Jahn-Teller distortion removal of band edge d-state degeneracies. These results identify a new and novel application for NEXAS based on the resonant character of the respective O K 1 and N K 1 edge absorptions. This paper also includes a brief discussion of the integration issues for the introduction of this Ge breakthrough into advanced semiconductor circuits and systems. This includes a comparison of nano-crystalline and non-crystalline dielectrics, as well as issues relative to metal gates.