Biodistribution of free 211At and 125I- in nude mice bearing tumors derived from anaplastic thyroid carcinoma cell lines.

UNLABELLED: Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC. METHODS: Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined. RESULTS: Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types. CONCLUSIONS: The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.

Preparation and biological evaluation of an astatine-211 labeled biotin conjugate: biotinyl-3-[211 At]astatoanilide.

Biotinyl-3-[211 At]astatoanilide ([211 At]AtBA) was prepared in more than 80% yield by destannylation. In vitro, [211 At]AtBA exhibited a high affinity for streptavidin, and was stable after incubation in human serum, cerebrospinal fluid and distilled water, whereas it was rapidly degraded in mouse serum. HPLC analysis showed that the main degradation pathway in mouse serum was the cleavage of [211 At]astatoaniline. In mice, [211 At]AtBA and its 125I-labeled analogue cleared rapidly from most tissues; however, there was some evidence for dehalogenation of both tracers.

Determination of absorbed dose to blood, kidneys, testes and thyroid in mice injected with 211At and comparison of testes mass and sperm number in x-irradiated and 211At treated mice.

Male mice were injected with 211At and the total absorbed dose to the whole blood, kidneys, testes and thyroid was determined. Extrapolation to man shows a close agreement with the predictions of the International Commission on Radiological Protection (ICRP) for the absorbed dose to human blood, kidneys and testes, but the absorbed dose to the thyroid is about 200 times greater than the ICRP prediction. Comparison of the reduction in testes mass and in sperm numbers 28 days after mice were injected with 211At, or exposed to x rays, indicates a factor of about four for the greater effectiveness of 211At alpha particles over 250 kVcp x rays for the induction of effects.

Characterization of At- species in simple and biological media by high performance anion exchange chromatography coupled to gamma detector.

Astatine is a rare radioelement belonging to the halogen group. Considering the trace amounts of astatine produced in cyclotrons, its chemistry cannot be evaluated by spectroscopic tools. Analytical tools, provided that they are coupled with a radioactive detection system, may be an alternative way to study its chemistry. In this research work, high performance anion exchange chromatography (HPAEC) coupled to a gamma detector (γ) was used to evaluate astatine species under reducing conditions. Also, to strengthen the reliability of the experiments, a quantitative analysis using a reactive transport model has been done. The results confirm the existence of one species bearing one negative charge in the pH range 2-7.5. With respect to the other halogens, its behavior indicates the existence of negative ion, astatide At(-). The methodology was successfully applied to the speciation of the astatine in human serum. Under fixed experimental conditions (pH 7.4-7.5 and redox potential of 250 mV) astatine exists mainly as astatide At(-) and does not interact with the major serum components. Also, the method might be useful for the in vitro stability assessment of (211)At-labeled molecules potentially applicable in nuclear medicine.

Evaluation of effects on the peritoneum after intraperitoneal α-radioimmunotherapy with (211)At.

The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70 µm) and the short half-life (7.21 h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.

Astatine (211At) as a therapeutic radionuclide. The plasma:blood cell distribution in vitro.

Therapy of carcinoma of the thyroid may include the use of the radionuclide 131I, which localizes to thyroid tissue. In considering the use of another halogen, the alpha particle emitting radionuclide astatine, 211At, there is also the requirement that it too can be taken up by the thyroid. However, in view of its short half-life (7.2 h) it is important that its transport in the blood is not a factor likely to render it less available. For example, retention of 211At by red cells may retard its uptake by the thyroid. This in vitro investigation of the partitioning of the 211At between erythrocytes and plasma indicates that it is not strongly bound by the red cells in blood.