Synthesis and preliminary in vitro evaluation of DOTA-Tenatumomab conjugates for theranostic applications in tenascin expressing tumors

Tenatumomab is an anti-tenascin murine monoclonal antibody previously used in clinical trials for delivering radionuclides to tumors by both pre-targeting (biotinylated Tenatumomab within PAGRIT) and direct ¹³¹Iodine labeling approaches. Here we present the synthesis and in vitro characterization of three Tenatumomab conjugates to bifunctional chelating agents (NHS-DOTA, NCS-DOTA and NCS-DTPA). Results indicate ST8198AA1 (Tenatumomab-DOTAMA, derived by conjugation of NHS-DOTA), as the most promising candidate in terms of conjugation rate and yield, stability, antigen immunoreactivity and affinity. Labeling efficiency of the different chelators was investigated with a panel of cold metals indicating DOTAMA as the best chelator. Labeling of Tenatumomab-DOTAMA was then optimized with several metals and stability performed confirms suitability of this conjugate for further development. ST8198AA1 represents an improvement of the previous antibody forms because the labeling with radionuclides like ¹⁷⁷Lu or ⁶⁴Cu would allow theranostic applications in patients bearing tenascin expressing tumors.     

Characterization of technetium(vII) reduction by cell suspensions of thermophilic bacteria and archaea

Washed cell suspensions of the anaerobic hyperthermophilic archaea Thermococcus pacificus and Thermoproteus uzoniensis and the anaerobic thermophilic gram-positive bacteria Thermoterrabacterium ferrireducens and Tepidibacter thalassicus reduced technetium [⁹⁹Tc(VII)], supplied as soluble pertechnetate with molecular hydrogen as an electron donor, forming highly insoluble Tc(IV)-containing grayish-black precipitate. Apart from molecular hydrogen, T. ferrireducens reduced Tc(VII) with lactate, glycerol, and yeast extract as electron donors, and T. thalassicus reduced it with peptone. Scanning electron microscopy and X-ray microanalysis of cell suspensions of T. ferrireducens showed the presence of Tc-containing particles attached to the surfaces of non-lysed cells. This is the first report on the reduction in Tc(VII) by thermophilic microorganisms of the domain Bacteria and by archaea of the phylum Euryarchaeota.     

Dosimetry in molecular nuclear therapy

Advanced personalized dosimetry for molecular nuclear therapy has been shown to be feasible in clinical practice. At the same time instrumentation and dosimetric software are still evolving at a high pace. Procedures developed so far differ in approach and sophistication, and standard operating procedures necessary for accurate patient specific dosimetry do not yet exist. For this reason we restricted ourselves to reviewing the literature and highlighting relevant developments.     

Contrasting accumulation biokinetics and distribution of Am, Co, Cs, Mn and Zn during the whole development time of the eggs of the common cuttlefish, Sepia officinalis

Cuttlefish eggs were exposed to ²⁴¹Am, Co, Cs, Mn and Zn for different periods of time during the 50-d of the embryonic development at 17 °C. Exposures were carried out using background dissolved concentrations of the metals, using the corresponding γ-emitting radiotracers (²⁴¹Am, ⁵⁷Co, ¹³⁴Cs, ⁵⁴Mn and ⁶⁵Zn). Eggs were then placed in non-contaminating conditions. Experiments allowed assessing 1) the uptake and depuration kinetics of the selected elements and 2) their distribution among the different egg compartments (i.e. eggshell, vitellus, peri-vitelline fluid and embryo). ²⁴¹Am, Co and Zn were accumulated continuously by the eggs all along the development time, whereas Mn reached saturation after one month of exposure. Interestingly, the uptake kinetics of Cs tightly followed the weight variation of the eggs, mainly because of water influx/outflux. During the first month of the embryonic life, ²⁴¹Am, Co, Cs, Mn and Zn remained associated with the eggshell, indicating that the latter acted as an efficient shield against their penetration. Nevertheless, from this time onwards, Co, Cs, Mn and Zn accumulated more or less efficiently in the embryo according to the following order: Cs > Zn > Mn > Co. ²⁴¹Am was the only element tested that did not cross the eggshell all along the exposure time. The depuration kinetics revealed that the retention capacity of the eggs varied during the embryonic life. The contrasting accumulation biokinetics are discussed in terms of chemical and biological processes occurring during the cuttlefish egg development.     

Quantitative comparison between the commercial software STRATOS® by Philips and a homemade software for voxel-dosimetry in radiopeptide therapy

BackgroundTargeted radionuclide therapy is a rapidly growing modality. A few commercial treatment planning systems are entering the market. However, some in-house systems are currently developed for a more flexible and customized dosimetry calculation at voxel-level. For this purpose, we developed a novel software, VoxelMed, and performed a comparison with the software STRATOS.MethodsThe validation of both of them was undertaken using radioactive phantoms with different volume inserts. A cohort of 10 patients was also studied after a therapeutic administration of ¹⁷⁷Lu-labelled radiopeptides. The activity, number of disintegrations, absorbed dose and dose-volume histogram (DVH) were calculated for the phantoms and the kidneys in patients, which were the main critical organs at risk in this study.ResultsIn phantoms the absorbed doses computed with VoxelMed and STRATOS agree within 5%. In patients at the voxel-level the absorbed dose to kidneys (VoxelMed: mean 0.66 Gy/GBq) showed a limited difference of 5%, but with a remarkable range (−40%, +60%) between the two software packages. Voxel-dosimetry allows to estimate the dose non-homogeneities in volumes, which may be evaluated through DVHs.ConclusionThis study demonstrates that a fully 3D voxel-dosimetry with multiple SPECT images is feasible by using home-made or commercial software package and absorbed dose results obtained are similar. The main difference between the studied tools was observed in the activity integration method (effective vs physical half-time to time activity curve tail). We believe that an effective half-time integration method produces a more accurate approximation of clinical uptake and resultant dosimetry.     

Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target

PurposeIn recent years the use of ⁶⁸Ga (t_1/2 = 67.84 min, β⁺: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of ⁶⁸Ga via the ⁶⁸Zn(p,n)⁶⁸Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand.MethodsIrradiations of 1.7 M solution of ⁶⁸Zn(NO₃)₂ in 0.2 N HNO₃ were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of ⁶⁷Ga through the ⁶⁸Zn(p,2n)⁶⁷Ga reaction. The product’s activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector.ResultsThe saturation yield of ⁶⁸Ga amounts to (330 ± 20) MBq/µA, corresponding to a produced activity of ⁶⁸Ga at the EOB of (4.3 ± 0.3) GBq in a typical production run at 46 µA for 32 min. The radionuclidic purity of the ⁶⁸Ga in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80–90%.ConclusionsIn summary, this approach provides clinically relevant amounts of ⁶⁸Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the ⁶⁸Ge/⁶⁸Ga generators.     

Répartiteur de dose des médicaments radiopharmaceutiques : contrôle qualité sur deux sites hospitaliers et comparaison avec la législation en vigueur en France

An increasing number of nuclear medicine departments are equipped with automated measurement systems for the preparation of radiopharmaceuticals, with the main aim of minimising technician's irradiation. However, the automatic measurement of the patient activity differs from the manual measurement in material and method. In this context, the objective of the present study was to test the performances of one of these systems, the Unidose by TRASIS^®, in two newly equipped hospitals. The particularity of these systems is they are made up of two dose calibrators: the entrance calibrator (well chamber) and the exit calibrator (probe). Controls were performed on both of these dose calibrators. The results obtained, as well as the methodology employed, were then compared with the regulatory requirements in France. The results found are coherent between the two sites and have highlighted several non-conformities compared to the current regulations, part of which concerning the carpule dose calibrator, which is actually a probe. These results raise the question of a suitable regulation for the new automated measurement systems in nuclear medicine.     

Illustrations cliniques en cardiologie

The examples and clinical cases presented in this section are not intended to be considered as absolute models in terms of image quality or device parameter settings. They must initiate an individual analysis according to CT parameters and image quality. Nevertheless, they present practically different CT levels which can be used according to the clinical context and the type of device.     

高压氧在放射性核素治疗大鼠种植癌后乏氧研究

目的:研究大鼠种植癌在高压氧(HBO)干预及放射治疗前后99mTc-HL91乏氧显像的变化,并探讨其与病理学改变之间的关系,为HBO联合放射性药物对恶性肿瘤治疗效果提供实验支持。方法:建立肿瘤株walker-256细胞大鼠皮下种植癌的动物模型,60只荷瘤大鼠随机分为四组:对照组,高压氧(HBO)组、胶体磷[32P]酸铬和HBO+胶体磷[32P]酸铬组。尾静脉注射99mTc-HL91 37MBq(0.1 mL),4 h后利用SPECT显像,计算肿瘤组织与对侧相应部位放射性计数比值(T/NT),显像当日游标卡尺测量肿瘤最大长径(a)和最大垂直横径(b),计算肿瘤体积以及治疗后不同时间的肿瘤生长率(f)。最后一次显像结束后处死全部模型大鼠,取肿瘤组织制成病理切片,观察各组大鼠肿瘤细胞的凋亡情况。比较实验各组T/NT与肿瘤生长率(f)以及凋亡的关系。结果:肿瘤99mTc-HL91显像良好,肿瘤部位与对侧相应部位具有较高的放射性计数比。治疗后大鼠肿瘤的乏氧区域及肿瘤体积均减少,以HBO+胶体磷[32P]酸铬组为著,T/NT与f呈正相关;大鼠肿瘤的细胞凋亡数明显高于对照组,以HBO+胶体磷[32P]酸铬组增加明显,治疗后T/NT与大鼠肿瘤细胞的凋亡数呈负相关。结论:HBO在放射性核素治疗大鼠种植癌中起到协同作用,通过99mTc-HL91乏氧显像观察HBO干预后胶体磷[32P]酸铬治疗肿瘤效果,从而为二者联合在肿瘤治疗的应用提供依据。     

Overview of commercial treatment planning systems for targeted radionuclide therapy

IntroductionTargeted Radionuclide Therapy (TRT) is a branch of cancer medicine dealing with the therapeutic use of radioisotopes associated with biological vectors accumulating in the tumors/targets, indicated as Molecular Radiotherapy (MRT), or directly injected into the arteries that supply blood to liver tumour vasculature, indicated as Selective RT (SRT). The aim of this work is to offer a panoramic view on the increasing number of commercially-available TRT treatment planning systems (TPSs).Materials and methodsA questionnaire was sent to manufacturers' representatives. Academic software were not considered. Questions were grouped as follows: general information, clinical workflow, calibration procedure, image processing/reconstruction, image registration and segmentation tools, time-activity curve (TAC) fitting and absorbed dose calculation.ResultsAll software reported have CE-marking. TPSs were divided between SRT-dedicated software [4] and MRT [5] dosimetry software. In SRT, since no kinetic process is involved, absorbed dose calculation does not require TAC fitting, and image registration is not fully developed in all TPS. All software requires a radionuclide-specific calibration. In SRT, a relative image calibration can be obtained by scaling the counts to a known activity. Automated VOI contouring and rigid/deformable propagation between different acquisitions time-points is implemented in most TPSs, although DICOM export is rare. Different TAC fits are available depending on the number of time-points. Voxel S-value and Local deposition methods are the most frequent dosimetric approaches; dose-voxel kernel convolution and semi-Monte Carlo method are also available.ConclusionsAvailable TPSs allows performing personalized dosimetry in clinical practice. Individual variations in methodology/algorithms must be considered in the standardisation/harmonization processes.