Free 211At Research Articles

Surface Adsorption of the Alpha-Emitter Astatine-211 to Gold Nanoparticles Is Stable In Vivo and Potentially Useful in Radionuclide Therapy

Targeted α-therapy (TAT) can eradicate tumor metastases while limiting overall toxicity. One of the most promising α-particle emitters is astatine-211 (211At). However, 211At-carbon bonds are notoriously unstable in vivo and no chelators are available. This hampers its adoption in TAT. In this study, the stability of 211At on the surface of gold nanoparticles (AuNPs) was investigated. The employed AuNPs had sizes in the 25–50 nm range. Radiolabeling by non-specific surface-adsorption in >99% radiochemical yield was achieved by mixing 211At and AuNPs both before and after polyethylene glycol (PEG) coating. The resulting 211At-AuNPs were first challenged by harsh oxidation with sodium hypochlorite, removing roughly 50% of the attached 211At. Second, incubation in mouse serum followed by a customized stability test, showed a stability of >95% after 4 h in serum. This high stability was further confirmed in an in vivo study, with comparison to a control group of free 211At. The AuNP-associated 211At showed low uptake in stomach and thyroid, which are hallmark organs of uptake of free 211At, combined with long circulation and high liver and spleen uptake, consistent with nanoparticle biodistribution. These results support that gold surface-adsorbed 211At has high biological stability and is a potentially useful delivery system in TAT.

Simulation of the distribution of astatine-211 solution dispersion in a lab room.

ObjectiveThis study aimed to evaluate the distribution of Astatine-211 (211At) solution dispersion in a small animal cage using autoradiography imaging to simulate the dispersion of 211At in a lab room to eventually prevent user’s risk of internal exposure in terms of radiation safety.Methods211At radiation sources with two chemical properties (Na211At and Free 211At) were prepared. The solutions of 211At were placed onto a dish with paper, and then, it was placed in a small animal cage for 3 h. After removing the dish, an imaging plate with attaching reference sources was placed at four walls of the cage for 15 h in a lead box. Imaging plates were read, and all pixel data were calculated using Microsoft Excel 2016 to obtain three-dimensional (3D) distribution. Calculated results were depicted using a 3D sphere model.ResultsThe mean activity of Free 211At was 2.3 times higher than that of Na211At on all autoradiography images. In the cage, the shape of the dispersion of Na211At was almost homogeneous, whereas that of Free 211At was more heterogeneous.ConclusionWe found that the solution of 211At vaporized naturally and was distributed heterogeneously in the cage, and the chemical properties of 211At influenced their behaviors. These results must be considered to minimize the risks of radiation safety.

Human dosimetry of free 211At and meta-[211At]astatobenzylguanidine (211At-MABG) estimated using preclinical biodistribution from normal mice

Background211At is one of the ideal nuclides for targeted radionuclide therapies (TRTs). Meta-[211At]astatobenzylguanidine (211At-MABG) has been proposed for the treatment of pheochromocytoma. To effectively use these radiopharmaceuticals, dosimetry must be performed. It is important to determine the absorbed doses of free 211At and 211At-MABG to determine the organs that may be at risk when using TRTs. The aim of this study was to estimate human dosimetry from preclinical biodistribution of free 211At and 211At-MABG in various organs in normal mice.MethodsMale C57BL/6 N mice were administered 0.13 MBq of free 211At or 0.20 MBq of 211At-MABG by tail-vein injection. The mice were sacrificed at 5 min, and at 1, 3, 6, and 24 h after the injection (n = 5 for each group). The percentage of injected activity per mass in organs and blood (%IA/g) was determined. The human absorbed doses of free 211At and 211At-MABG were calculated using the Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) version 2.0 and IDAC-Dose 2.1.ResultsHigh uptake of free 211At was observed in the lungs, spleen, salivary glands, stomach, and thyroid. The absorbed doses of free 211At in the thyroid and several tissues were higher than those of 211At-MABG. The absorbed doses of 211At-MABG in the adrenal glands, heart wall, and liver were higher than those of free 211At.ConclusionsThe absorbed doses of 211At-MABG in organs expressing the norepinephrine transporter were higher than those of free 211At. In addition, the biodistribution of free 211At was different from that of 211At-MABG. The absorbed dose of free 211At may help predict the organs potentially at risk during TRTs using 211At-MABG due to deastatination.

Preliminary Evaluation of Astatine-211-Labeled Bombesin Derivatives for Targeted Alpha Therapy.

There are various diagnostic and therapeutic agents for prostate cancer using bombesin (BBN) derivatives, but astatine-211 (211At)-labeled BBN derivatives have yet to be studied. This study presented a preliminary evaluation of 211At-labeled BBN derivative. Several nonradioactive iodine-introduced BBN derivatives (IB-BBNs) with different linkers were synthesized and their binding affinities measured. Because IB-3 exhibited a comparable affinity to native BBN, [211At]AB-3 was synthesized and the radiochemical yields of [211At]AB-3 was 28.2 ± 2.4%, with a radiochemical purity of >90%. The stability studies and cell internalization/externalization experiments were performed. [211At]AB-3 was taken up by cells and internalized; however, radioactivity effluxed from cells over time. In addition, the biodistribution of [211At]AB-3, with and without excess amounts of BBN, were evaluated in PC-3 tumor-bearing mice. Despite poor stability in murine plasma, [211At]AB-3 accumulated in tumor tissue (4.05 ± 0.73%ID/g) in PC-3 tumor-bearing mice, which was inhibited by excess native BBN (2.56 ± 0.24%ID/g). Accumulated radioactivity in various organs is probably due to free 211At. Peptide degradation in murine plasma and radioactivity efflux from cells are areas of improvement. The development of 211At-labeled BBN derivatives requires modifying the BBN sequence and preventing deastatination.

Sensitivity to a poly(ADP-ribose) Polymerase 1 (PARP-1) Targeting Alpha Particle Therapeutic in Neuroblastoma Is Characterized by Increased Relative Biological Effectiveness (RBE) Compared to Gamma Irradiation

Neuroblastoma is the most common extracranial solid malignancy in childhood, with only up to 50% 5-year survival in high-risk cases. Neuroblastoma overexpresses the nuclear enzyme PARP-1, which can be targeted for specific delivery of alpha particles to DNA using an astatine-211 radiolabeled small molecule PARP-1 inhibitor called [211At]MM4. Using a panel of twenty human neuroblastoma cell lines previously screened in vitro for sensitivity to [211At]MM4, IMR5 and NLF were chosen as examples of a sensitive and a resistant cell line to assess RBE. Next, radiopharmacologic properties of the two cell lines were characterized by performing radioligand saturation binding assays to measure the maximum number of binding sites for [211At]MM4 and to directly measure bound [211At]MM4. For self-dose calculation, the geometric dimensions of the cells were measured by immunofluorescence microscopy. For cross-dose calculation, the cellular arrangements in the sensitivity screening condition was modeled with hexagonal circle packing. Then, Monte Carlo simulation was performed with MIRDcell v2.0 to calculate the total radiation dose to the cell nucleus from astatine-211 and its daughters at 50% cell kill (D50). RBE against gamma rays was calculated using D50 for gamma irradiation with a cesium-137 source. Finally, mouse tumor xenograft models were imaged with 18F-fluorthanatrace (FTT), a [211At]MM4 analog for positron emission tomography (PET), for correlative in vivo dosimetry. In IMR5 cells, [211At]MM4 demonstrated 3 and 9 orders of magnitude greater cytotoxic potency compared to free 211At and its non-radioactive analog respectively, whereas the differences were 2 and 8 orders of magnitude in NLF. IMR5 had more PARP-1 binding sites compared to NLF (Bmax= 2.3 vs 1.4 million sites/cell), but similar binding affinity of [211At]MM4 was seen (IMR5: Kd=2.7 nM, NLF: Kd=2.4 nM). The nuclear and cell radii were measured at 6 μm and 8 μm respectively in IMR5, and 9 μm and 12 μm in NLF. The mean distance between adjacent cells was determined to be 86 μm. The D50 in IMR5 was 0.076 Gy for [211At]MM4, 0.34 Gy for free 211At, and 0.7 Gy for gamma irradiation, yielding RBE of 9.2 for [211At]MM4. The D50 in NLF was 3.8 Gy for [211At]MM4, 4.6 Gy for 211At, and 3.6 Gy for gamma irradiation, yielding RBE of 1.0. Using 18F-FTT mouse PET images, the tumor radiation dose from [211At]MM4 based on tumor size and amount of [211At]MM4 administered were modelled. Delivery of an alpha emitter directly to the neuroblastoma nuclear DNA by the astatinated PARP-1 inhibitor [211At]MM4 results in variable levels of enhanced cytotoxicity. Sensitivity to [211At]MM4 is characterized by increased RBE against gamma irradiation, warranting investigation of the underlying biological factors. Tumor dosimetry results from mouse models can be applied to future in vivo therapy experiments with [211At]MM4 for correlation between tumor dose and therapeutic efficacy.

Biodistribution and Dosimetry of Free 211At and Meta-[211At]astatobenzylguanidine (MABG) in Normal Mice

Biodistribution and Dosimetry of Free 211At and Meta-[211At]astatobenzylguanidine (MABG) in Normal Mice

Sensitivity to a poly(ADP-ribose) Polymerase 1 (PARP-1) Targeting Alpha Particle Therapeutic in Neuroblastoma Is Characterized by Increased Relative Biological Effectiveness (RBE) Compared to Gamma Irradiation

Neuroblastoma is the most common extracranial solid malignancy in childhood, with only up to 50% 5-year survival in high-risk cases. Neuroblastoma overexpresses the nuclear enzyme PARP-1, which can be targeted for specific delivery of alpha particles to DNA using an astatine-211 radiolabeled small molecule PARP-1 inhibitor called [211At]MM4. Using a panel of twenty human neuroblastoma cell lines previously screened in vitro for sensitivity to [211At]MM4, IMR5 and NLF were chosen as examples of a sensitive and a resistant cell line to assess RBE. Next, radiopharmacologic properties of the two cell lines were characterized by performing radioligand saturation binding assays to measure the maximum number of binding sites for [211At]MM4 and to directly measure bound [211At]MM4. For self-dose calculation, the geometric dimensions of the cells were measured by immunofluorescence microscopy. For cross-dose calculation, the cellular arrangements in the sensitivity screening condition was modeled with hexagonal circle packing. Then, Monte Carlo simulation was performed with MIRDcell v2.0 to calculate the total radiation dose to the cell nucleus from astatine-211 and its daughters at 50% cell kill (D50). RBE against gamma rays was calculated using D50 for gamma irradiation with a cesium-137 source. Finally, mouse tumor xenograft models were imaged with 18F-fluorthanatrace (FTT), a [211At]MM4 analog for positron emission tomography (PET), for correlative in vivo dosimetry. In IMR5 cells, [211At]MM4 demonstrated 3 and 9 orders of magnitude greater cytotoxic potency compared to free 211At and its non-radioactive analog respectively, whereas the differences were 2 and 8 orders of magnitude in NLF. IMR5 had more PARP-1 binding sites compared to NLF (Bmax= 2.3 vs 1.4 million sites/cell), but similar binding affinity of [211At]MM4 was seen (IMR5: Kd=2.7 nM, NLF: Kd=2.4 nM). The nuclear and cell radii were measured at 6 μm and 8 μm respectively in IMR5, and 9 μm and 12 μm in NLF. The mean distance between adjacent cells was determined to be 86 μm. The D50 in IMR5 was 0.076 Gy for [211At]MM4, 0.34 Gy for free 211At, and 0.7 Gy for gamma irradiation, yielding RBE of 9.2 for [211At]MM4. The D50 in NLF was 3.8 Gy for [211At]MM4, 4.6 Gy for 211At, and 3.6 Gy for gamma irradiation, yielding RBE of 1.0. Using 18F-FTT mouse PET images, the tumor radiation dose from [211At]MM4 based on tumor size and amount of [211At]MM4 administered were modelled. Delivery of an alpha emitter directly to the neuroblastoma nuclear DNA by the astatinated PARP-1 inhibitor [211At]MM4 results in variable levels of enhanced cytotoxicity. Sensitivity to [211At]MM4 is characterized by increased RBE against gamma irradiation, warranting investigation of the underlying biological factors. Tumor dosimetry results from mouse models can be applied to future in vivo therapy experiments with [211At]MM4 for correlation between tumor dose and therapeutic efficacy.

Biodistribution and Dosimetry of Free 211At and Meta-[211At]astatobenzylguanidine (MABG) in Normal Mice

Biodistribution and Dosimetry of Free 211At and Meta-[211At]astatobenzylguanidine (MABG) in Normal Mice

Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment

Octreotide is a somatostatin (SST) analogue currently used in the treatment of neuroendocrine tumors (NETs) with high binding affinity for the somatostatin receptor-2 (SSTR2) that is also overexpressed in non-small cell lung cancer cell (NSCLC). Alpha-particle-emitting astatine-211 (211At) is a promising radionuclide with appropriate physical and chemical properties for use in targeted anticancer therapies. To obtain an additional pharmacological agent for the treatment of NSCLC, we present the first investigation of the possible use of 211At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for NSCLC treatment. 211At-SPC-octreotide exhibited observable higher uptake in lung, spleen, stomach and intestines than in other tissues. Through histological examination, 211At-SPC-octreotide demonstrated much more lethal effect than control groups (PBS, octreotide and free 211At). These promising preclinical results suggested that 211At labeled octreotide deserved to be further developed as a new anticancer agent for NSCLC.

Biodistribution and Dosimetry of Free 211At, 125I− and 131I− in Rats

131I is widely used for therapy in the clinic and 125I and 131I, and increasingly 211At, are often used in experimental studies. It is important to know the biodistribution and dosimetry for these radionuclides to determine potential risk organs when using radiopharmaceuticals containing these radionuclides. The purpose of this study was to investigate the biodistribution of 125I-, 131I-, and free 211At in rats and to determine absorbed doses to various organs and tissues. Male Sprague Dawley rats were injected simultaneously with 0.1-0.3 MBq 125I- and 0.1-0.3 MBq 131I-, or 0.05-0.2 MBq 211At and sacrificed 1 hour to 7 days after injection. The activities and activity concentrations in organs and tissues were determined and mean absorbed doses were calculated. The biodistribution of 125I- was similar to that of 131I- but the biodistribution of free 211At was different compared to 125I- and 131I-. The activity concentration of radioiodine was higher compared with 211At in the thyroid and lower in all extrathyroidal tissues. The mean absorbed dose per unit injected activity was highest to the thyroid. 131I gave the highest absorbed dose to the thyroid, and 211At gave the highest absorbed dose to all other tissues studied.

211At-AntiCD33 in NMRI nu/nu mice

SummaryThe aim of this study is to verify the in vivo stability, to determine the biodistribution and to estimate the unspecific radiotoxicity of an 211At-labelled CD33-antibody (211At-anti-CD33) in mice with a view to therapeutic application in treating leukaemia. Animals, methods: 211At was produced via the 209Bi(α,2n)211At reaction and was linked via 3-211At-succinimidyl-benzoate to the anti-CD33-antibody. The biodistribution and the in vivo stability in serum were determined after i.v.-injection in NMRI nu/nu-mice. For toxicity experiments, mice received either three times 315–650 kBq 211At-antiCD33 or unlabelled antibody and NaCl-solution respectively. Results: 211At-antiCD33 showed a characteristic biodistribution complying with the unspecific antibody retention in the reticular endothelial system. The largest proportion of radioactivity remained in blood and blood-rich tissues with a minor accumulation in the thyroid and stomach. After 21 h, > 85% of activity in serum still represented intact antibody. Mice showed no difference in unspecific toxicity of 211At-labelled antibodies over six months compared to those treated with unlabelled antibody and NaCl-solution respectively, with regard to histopathologic lesions, survival time, behaviour and haemograms. Conclusion: The radiolabelling method yielded adequate in vivo stability of 211At-antiCD33. Biodistribution with rapid elimination of free 211At via kidneys and urine complies with requirements for targeted therapy. Activity doses potentially required for treatment do not elicit radiotoxicity to normal organs in mice. Further development is required to enhance the apparent specific activity and to verify the efficacy in an adequate animal model before phase I clinical studies in leukaemia can be envisaged.

Biodistribution of211At-Labeled Humanized Monoclonal Antibody A33

Radioimmunotherapy (RIT) could be a possible adjuvant treatment method for patients with colorectal carcinoma. The A33 antigen is a promising RIT target, as it is highly and homogenously expressed in 95% of all colorectal carcinomas. In this study, the humanized monoclonal antibody A33 (huA33), targeting the A33 antigen, was labeled with the therapeutic nuclide 211At, and the biodistribution and in vivo targeting ability of the conjugate was investigated in an athymic mouse xenograft model. There was an accumulation of 211At in tumor tissue over time, but no substantial accumulation was seen in any organ apart from the skin and thyroid, indicating no major release of free 211At in vivo. At all time points, the uptake of 211At-huA33 was higher in tumor tissue than in most organs, and at 8 hours postinjection (p.i.), no organ had a higher uptake than tumor tissue. The tumor-to-blood ratio of 211At-huA33 increased with time, reaching 2.5 after 21 hours p.i. The highest absorbed dose was found in the blood, but the tumor received a higher dose than any organ other than the thyroid. An in vivo blocking experiment showed that 211At-huA33 binds specifically to human tumor xenografts in athymic mice. In conclusion, the favorable biodistribution and specific in vivo targeting ability of 211At-huA33 makes it a potential therapeutic agent for the RIT of metastatic colorectal carcinoma.

Transport of free 211At and 125I− in thyroid epithelial cells: effects of anion channel blocker 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid on apical efflux and cellular retention

Astatine ((211)At; alpha-emitter; t(1/2)=7.21 h) shares several features with its halogen neighbour iodine. In the present study, we investigated whether 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) can be used to increase the cellular retention time of (211)At and radioiodide in thyroid epithelial cells. The transepithelial transport and cellular uptake of (211)At and (125)I(-) were studied simultaneously in porcine thyrocytes cultured in bicameral chambers. The cells were prestimulated with thyroid-stimulating hormone (TSH) or epidermal growth factor (EGF) for 48 h. In addition, the acute effects of DIDS and forskolin were investigated. The transepithelial transport of both radionuclides was stimulated by TSH and down-regulated by EGF. DIDS rapidly reduced the efflux and increased the cellular content of (125)I(-) in control and TSH-stimulated cells, whereas DIDS had no effect on (125)I(-) transport in EGF-treated cells. DIDS blocked the (211)At efflux only in TSH-stimulated cells. Unexpectedly, DIDS caused an accelerated efflux of (211)At in both control and EGF-stimulated cells and, furthermore, reduced the cellular content of (211)At in the EGF-stimulated cultures. DIDS had no effect on the forskolin-induced efflux of the two radionuclides. The magnitude of thyroidal (211)At uptake and efflux is similar to that of (125)I(-), strongly dependent on the functional activity of the cells. However, (211)At efflux likely involves several permeating mechanisms with different sensitivity to DIDS, which are at least partly not shared by (125)I(-). The results suggest that anion channel blockage is potentially useful to increase the absorbed dose from both (211)At and radioiodine in NIS-expressing tumours.

Biodistribution of 211At labeled HER-2 binding affibody molecules in mice

The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the alpha-emitter 211At, since their biokinetic properties match the short physical half-live of 211At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumor-bearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125I, the 211At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.

Biodistribution of Free 211At and 125I– in Nude Mice Bearing Tumors Derived from Anaplastic Thyroid Carcinoma Cell Lines

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. 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. 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. 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.

Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab′)2

To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2. Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy. As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.

Adsorption and volatility of free 211At and 125[formula omitted

The present study was undertaken to extend our knowledge of the behaviour of 211At in the laboratory environment. An unexpectedly high volatility of free 211At was found, up to 85% during an hour. Free 211At also adsorbed more onto the plastic material studied than 125I-. The results of this study show that it is of great importance to pay careful attention to radiation protection procedures during the practical handling of free 211At.

Microdosimetry of astatine-211 single-cell irradiation: Role of daughter polonium-211 diffusion

A microdosimetric analysis of previously published data on 211At-albumin, free 211At, and 211At-C215 irradiation of Colo-205 cells in a slowly rotating single-cell suspension is presented. A custom-built computer program based on the Monte Carlo method was used to simulate the irradiation and the energy deposition in individual cell nuclei. Separate simulations were made for the assumption that the 211Po atom stays in the position where it is created, and that it diffuses away. The mean event number at which 37% of all cells survived, n37, and the frequency mean specific energy per event, zF, were estimated. The Poisson distribution of events and simulated single and multievent distributions of specific energy were used to find the single-cell specific energy at which the probability of survival is reduced to 37%, z37. The calculated single-cell radiosensitivity values show that 211Po atoms, created on a cell surface by the decay of 211At atoms, will diffuse from the cell during its life-span. The increasing distance to the cell nucleus will drastically decrease the probability of the emitted alpha particle to hit the nucleus. This will result in fewer alpha-particle events in the cell nucleus. For dispersed cells, the diffusion of 211Po atoms will reduce the total dose from cell-bound 211At by a factor of 2.

Similarities and differences between free 211At and 125I− transport in porcine thyroid epithelial cells cultured in bicameral chambers

The transport and accumulation of free 211At and 125I− were investigated in thyrocytes cultured as monolayers in bicameral chambers under the influence of thyroid-stimulating hormone, stable iodide, ouabain and perchlorate. The results indicate that there are similarities and differences in the transport mechanisms of free 211At and 125I−. These results will be valuable in the development of radiation protection when handling and using 211At-labeled radiopharmaceuticals, and for the potential use of free 211At in radiation therapy of poorly differentiated thyroid cancer.

α-Particle Radiotherapy with 211At-Labeled Monodisperse Polymer Particles, 211At-Labeled IgG Proteins, and Free 211At in a Murine Intraperitoneal Tumor Model

Four different chemical forms of the α-particle emitting radionuclide 211 At were injected intraperitoneally in mice inoculated intraperitoneally 30 hr in advance with 106 cells of the K13 murine hybridoma cell line. The different 211At forms were (a) free 211At, (b) 211At-labeled TP-3 nonspecific monoclonal antibody (211At-TP-3), (c) 211At-labeled human IgGκ (211At-hIgGκ), and (d) 211At-labeled monodisperse polymer particles (211At-MDPP). A significantly prolonged survival (P < 0.05) was observed with injected doses down to 7 kBq for the 211 At-MDPP, and down to 25 kBq for 211At-hIgGκ. There were no significant differences in survival between 211 At-MDPP, 211At-hIgGκ, and 211At-TP-3 at the dose level of 200 kBq. The group receiving 250 kBq free 211At per animal had a shorter survival than the three other forms at 200 kBq. The groups treated with 500, 200, and 65 kBq 211At-MDPP had a similar survival. The group given the highest dose of 211At-hIgGκ (275 kBq) had the highest fraction (50%) of long-term survivors of all groups. Biodistribution measurements and total body scintigrams in mice without tumor revealed that the free 211At was distributed all over the body within 10 min after injection while at 2 hr a high fraction of the 211 At-TP-3 and 211At-hIgGκ was still present intraperitoneally. In conclusion this study indicates that 211 At-labeled MDPP and 211At-labeled IgG's may be efficient tools for treatment of intraperitoneal superficial tumor cells and malignant ascites.