Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.

Radiation doses to non-Hodgkin's lymphoma cells and normal bone marrow exposed in vitro. Comparison of an alpha-emitting radioimmunoconjugate and external gamma-irradiation.

PURPOSES: The alpha-emitting radionuclide 211At conjugated to the CD20 targeting chimeric monoclonal antibody rituximab was studied to: (a) Estimate radiation dose components to lymphoma and bone marrow (BM) cells exposed in vitro. (b) Calculate the mean absorbed radiation doses in various normal tissues of mice following intravenous injection. MATERIALS AND METHODS: B-lymphoma cells (RAEL) and normal human BM cells were incubated with increasing concentrations of the radioimmunoconjugate. Based on binding kinetics and on measured cellular and nuclear diameters, the radiation doses were calculated using microdosimetric methods. RESULTS: Targeting of 211At-rituximab to RAEL cells was extensive and stable compared with the binding to BM cells. The absorbed radiation doses from cell-bound activity at an initial activity concentration of 10 kBq ml(-1) were 0.645 and 0.021 Gy to RAEL and BM cells, respectively. In comparison, the contribution from unbound conjugate in the medium during 1h exposure was 0.042 and 0.043 Gy. The D(0) value for RAEL cells was 0.55 Gy, but only 0.34 Gy for BM cells, whereas corresponding D(0) values were 0.72 and 1.21 Gy after a single exposure to external 60Co gamma-rays. Mean absorbed doses of 1.31, 0.48 and 0.36 Gy for blood, lungs and heart were calculated in mice injected with 5.4kBq g(-1) of 211At-rituximab. CONCLUSION: Despite the higher inherent sensitivity of the BM cells to the alpha-irradiation, there was, related to the radioactivity concentrations of 211At-rituximab, several logs greater cell kill in RAEL cells, illustrating the tumour-specific nature of the targeting.

Optimisation of cyclotron production parameters for the 209Bi(alpha, 2n) 211At reaction related to biomedical use of 211At.

The cyclotron alpha beam production of 211At and of the contaminant 210At related to beam energy were studied. Radiochemical purification of 211At from the other main contaminant, 210Po, by an extraction procedure was also evaluated. To avoid impurities 28MeV has previously been considered as a maximum beam energy, but by using instead 29.1 MeV as a limit a large increase in EOB yield and sufficient radiochemical purity of extracted 211At were obtained. More cyclotrons could thereby deliver quantities useful for clinical cancer trials.

Demonstration of highly specific toxicity of the alpha-emitting radioimmunoconjugate(211)At-rituximab against non-Hodgkin's lymphoma cells.

The ability of an alpha-emitter conjugated to a chimaeric anti-CD20 monoclonal antibody to kill selectively human B-lymphoma cells in vitro is reported. Two B-lymphoma cell lines RAEL and K422, and normal haematopoietic progenitor cells from human bone marrow aspirates were incubated with(211)At-rituximab (Rituxan(R) or MabTheratrade mark) and plated in clonogenic assays for survival analyses. Following 1 h incubation with(211)At-rituximab, in concentrations which gave an initial activity of 50 kBq ml(-1), a high tumour cell to normal bone marrow cell toxicity ratio was obtained; 4.1 to 1.0 log cell kill. Biodistribution studies of(211)At-rituximab in Balb/c mice showed similar stability as that of the iodinated analogue. The data indicate that testing of(211)At-rituximab in human patients is warranted.

Exposure of human osteosarcoma and bone marrow cells to tumour-targeted alpha-particles and gamma-irradiation: analysis of cell survival and microdosimetry.

PURPOSE: This study was designed to compare the cytotoxic effects of an alpha-emitting radioimmunoconjugate, which binds to osteosarcoma but not to bone marrow cells, with those of external gamma-irradiation. MATERIALS AND METHODS: The human osteosarcoma cell line, OHS-s1, and mononuclear cells from bone marrow (BM) harvested from healthy donors, were used for these experiments. Cells in suspension were added to various activity concentrations of the anti-osteosarcoma monoclonal antibody TP-3 radiolabelled with 211At. Following incubation for 1 h, unbound radioactivity was washed off and cell survival was determined from clonogenic assays. Microdosimetry was calculated based on binding and retention kinetics of 211At to the cells, as well as cellular and nuclear diameters. For comparison, cell suspensions were irradiated with a single dose of 60Co gamma-rays. RESULTS: 211At-labelled TP-3 showed heterogeneous binding to OHS-s1 cells, with a considerable variation among experiments. About 78% of the initially bound 211At decayed while associated with the OHS-s1 cells. D0 values estimated by microdosimetry were 0.33 (0.22-0.48, range) Gy and 1.18 (0.89-1.89) Gy for OHS-s1 and BM cells, respectively, whereas D0 values after external beam irradiation were 0.86+/-0.07Gy and 1.71+/-0.22Gy. The relative biological effectiveness (RBE) of 211At-labelled TP-3 at 37% survival was 3.43 for OHS-s1 and 1.55 for BM. CONCLUSIONS: High-LET targeted alpha-particle exposure killed osteosarcoma cells more effectively than bone marrow cells, although heterogeneous antigen expression among these tumour cells limited the magnitude of this effect.

Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis.

PURPOSE: The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated. METHODS AND MATERIALS: Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year. RESULTS: The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody. CONCLUSIONS: The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with 211At-labeled chimeric 81C6.

211At- and 131I-labeled bisphosphonates with high in vivo stability and bone accumulation.

UNLABELLED: Bisphosphonates were synthesized for use as carriers for astatine and iodine radioisotopes to target bone neoplasms. METHODS: Radiohalogenated activated esters were coupled to the amino group in the side chain of the bisphosphonate. The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with four different acylation agents: N-succinimidyl 3-[211At]astatobenzoate, N-succinimidyl 3-[131I]iodobenzoate, N-succinimidyl-5-[211At]astato-3-pyridinecarboxylate and N-succinimidyl-5-[131I]iodo-5-pyridinecarboxylate. The products, 3-[131I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB), 3-[211At]astato-benzamide-N-3-hydroxypropylidene-3,3-bisphosphonat e (ABPB), 5-[131I]iodopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphospho nate (IPPB) and 5-[211At]astatopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphos phonate (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo methods were used on the basis of cumulated activity calculated from biodistribution data to estimate dose to organs and bone segments. RESULTS: All 131I- and 211At-labeled analogs were strongly incorporated into osseous tissue and retained there at stable levels, while a rapid clearance from blood was observed. The bone uptake was found to be similar for 211At- and 131I-labeled bisphosphonate when compared in paired label experiments. Bone uptake and bone-to-tissue ratios were better for IBPB compared with IPPB, and ABPB compared with APPB. All four compounds appeared to be highly resistant to in vivo dehalogenation as indicated by low uptake of 131I/211At in the thyroid gland and stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio was three times higher with 211At than with 131I. CONCLUSION: Both the beta-particle- and alpha-particle-emitting compounds showed high in vivo stability and excellent affinity for osseous tissue. Further preclinical evaluation is therefore warranted.

Synthesis, purification, and in vitro stability of 211At- and 125I-labeled amidobisphosphonates.

A method is described for preparing 211At- and radioiodinated amidobisphosphonates. The active esters N-succinimidyl 3-(tri-methylstannyl) benzoate (ATE) and N-succinimidyl 5-(tri-methylstannyl)-3-pyridinecarboxylate (SPC) were used as precursors. The isolated and purified radiolabeled intermediates were coupled to 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB) in high yields ranging from 60% to 97%. The lipophilicity of the compounds was found to depend on the nature of the labeled template and the halogen. High in vitro stability in mouse, fetal calf, and human serum was documented by high performance liquid chromatography.

Influence of pretreatment with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB) on organ uptake of 211At and 125I-labeled amidobisphosphonates in mice.

To minimize nontarget organ uptake in animals receiving radiolabeled amidobisphosphonates, the influence of pretreatment with cold 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB, pamidronate) was studied. Three groups of animals were given pure 3-[125I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB) and 3-[211At]astatobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (ABPB) (control); co-injection of APB and IBPB/ABPB; and 1 h preinjection of APB followed by IBPB/ABPB, respectively. A significant reduction of uptake in normal tissue was observed, whereas the bone uptake remained constant at 35-50%ID/g tissue. This study suggests that co- or preinjection of pamidronate may reduce the normal organ radiation doses when using these radiohalogenated bisphosphonates for endoradiotherapeutic procedures.

Blocking [211At]astatide accumulation in normal tissues: preliminary evaluation of seven potential compounds.

Normal tissue accumulation of 211At must be minimized during targeted radiotherapy with 211At-labeled compounds. Therefore, we investigated the ability of seven compounds to block normal organ uptake of [211At]astatide in mice: potassium iodide, sodium thiocyanate, sodium perchlorate, sodium periodate, cysteine, 2,3-dimercapto-1-propanesulfonic acid, and meso-2,3-dimercaptosuccinic acid. The monovalent anions I-, SCN-, and ClO4- reduced 211At uptake in stomach and thyroid, while thiocyanate and cysteine were the only compounds to significantly reduce activity levels in lungs and spleen. This study suggests that blocking agents may help reduce normal organ radiation doses in endoradiotherapeutic procedures with 211At-labeled radiopharmaceuticals.

Intratumour injection of immunoglobulins labelled with the alpha-particle emitter 211At: analyses of tumour retention, microdistribution and growth delay.

To determine the effects of 211At-labelled antibodies in solid tumour tissue, nude mice carrying OHS human osteosarcoma xenografts received intratumour injections at dosages of 1, 2 or 4 MBq (-1) tumour. The radioisotope was conjugated to either the osteosarcoma-specific monoclonal antibody TP-3 or the non-specific polyclonal antibody hlgGkappa. Tumour retention of injected radioimmunoconjugate (RIC), measured as the percentage of injected activity dosage per gram, was significantly higher for the [211At]TP-3 (203 +/- 93 at 24.1 h post injection) compared with the [211At]hlgGkappa (57 +/- 22 at 23.2 h post injection). The radioactive count rates in body (measured at neck and abdomen) were significantly lower with the TP-3 than with the hlgGkappa. Microautoradiography of the tumour radionuclide distribution was different for the two RICs, i.e. the [211At]TP-3 was to a larger extent concentrated near the injection site, whereas the [211At]hlgGkappa was more evenly distributed all over the tumour. The tumour growth was significantly delayed as a function of the injected activity dosage but without significant difference between the specific and the non-specific RIC. According to this study, it is possible to deliver highly selective radiation doses to solid tumours using intratumour injection of alpha-particle-emitting RICs. Improved tumour retention caused by antigen binding indicates that reduced normal tissue exposure can be obtained with antigen-specific antibodies. The heterogeneous tumour dose distribution observed is, however, a major impediment to the use of alpha-particle emitters against solid tumours.

Cytotoxicity of alpha-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia.

The high linear energy transfer, alpha-particle-emitting radionuclide astatine-211 (211At) is of interest for certain therapeutic applications; however, because of the 55- to 70-microm path length of its alpha-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of alpha-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 211At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 microm) greater than the range of 211At alpha-particles. Hyperthermia for 1 h at 42 degrees C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml(-1). A significant regrowth delay was observed at 125 and 250 kBq ml(-1) in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 42 degrees C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids.

The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro.

The cytotoxicity of alpha-particle-emitting endoradiotherapeutic compounds is of increasing interest because clinical evaluation of these potential therapeutic agents is commencing. Astatine-211 is a radionuclide with a 7.2-h half-life that emits 5.87 and 7.45 MeV alpha particles. In the present work, we have investigated the in vitro cytotoxicity of 211At-labeled chimeric monoclonal antibodies (mAbs) in monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. The mAbs studied were 81C6, reactive with the extracellular matrix antigen tenascin, Mel-14, directed against the cell membrane antigen proteoglycan chondroitin sulfate, and a nonspecific control mAb, TPS3.2. Cell uptake increased as a function of activity concentration after a 1-h exposure to the 211At-labeled mAbs. The retention of activity was also measured to calculate cumulative activity associated with the cells and the medium. The clonogenic survival as a function of activity concentration was linear in all cases with no detectable shoulder. Microdosimetric analyses were performed based on measured cell geometry, cumulative activity and Monte Carlo transport of alpha particles. Using 18 kBq/ml activity concentration and 1 h of incubation, a two to five times higher activity bound to the microcolonies was found for the specific mAbs compared to the nonspecific mAb. These calculations indicated that a survival fraction of 0.37 was achieved with 0.24-0.28 Gy for D-247 MG cells and 0.27-0.29 Gy for SK-MEL-28 cells. The microdosimetric cell sensitivity, z0, for D-247 MG cells was significantly lower than for SK-MEL-28 cells (0.08 compared to 0.15 Gy). For both cell lines, reduction in survival to 0.37 required an average of only 1-2 alpha-particle hits to the cell nucleus.

Cytotoxicity of alpha-particle-emitting 5-[211At]astato-2'-deoxyuridine in human cancer cells.

This study was performed to determine the cytotoxicity of alpha-particle-emitting 5-[211At]astato-2-deoxyuridine (i.e. [211At]AUdR) for monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. Cells in exponential growth were exposed to varying activity concentrations of [211At]AUdR and for comparison [211At]astatide and the Auger electron-emitting analogue, 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR). Cell uptake, DNA binding and clonogenic survival as a function of activity concentration in the medium were determined following 2 and 20-h incubations. None of the survival curves had detectable shoulders, an observation consistent with high-LET effects. The A37 (initial activity concentration yielding 37% cell survival) were significantly lower for both cell lines following 20-h exposure of [211At]AUdR than [211At]astatide. After correcting for effects from non-cell-associated activity in the medium, the specific cytotoxicity of cell-associated and DNA-bound [211At]AUdR was estimated. In the 20-h incubation experiments, the A37 for DNA-associated [211At]AUdR corresponded to about one 211At atom bound per cell for both cell lines. Unlike [211At]AUdR, there was a biphasic survival response to [125I]IUdR, consistent with the lower fractional uptake of [125I]IUdR at higher activity concentrations. These studies suggest that [211At]AUdR warrants further evaluation as an endoradiotherapeutic agent for the treatment of rapidly proliferating cancers.

Serological assays for the identification of Oesophagostomum dentatum infections in pigs.

Oesophagostomum dentatum antigen preparations of third (L3) or fourth (L4) stage larvae were characterised by Western blotting. Panels of sera obtained from pigs infected with O dentatum and Ascaris suum, respectively, reacted with the same bands of L3 antigen. In contrast high specificity against a characteristic band, was observed when L4 extract was employed as antigen. To establish an enzyme-linked immunosorbent assay (ELISA), a panel of homologous and heterologous sera was tested against O dentatum L4 extract. The best combined specificity and sensitivity was obtained when horseradish peroxidase (HRP) goat anti swine IgG conjugate was used rather than HRP rabbit anti swine Ig conjugate. Testing series of sera from pigs infected with single doses of either 2000, 20,000 or 200,000 infective larvae by the ELISA, a significant dose dependency in the antibody response was observed between the low and high dosage groups. This assay may be useful in future studies of the immune-mechanisms against nodular worm infections in pigs.

Tissue distribution and radiation dosimetry of astatine-211-labeled chimeric 81C6, an alpha-particle-emitting immunoconjugate.

A paired-label study was performed in athymic mice bearing subcutaneous D-54 MG human glioma xenografts to compare the localization of human/mouse anti-tenascin chimeric antibody 81C6 labeled by reaction with N-succinimidyl 3-[211At]astatobenzoate and N-succinimidyl 3-[131I]iodobenzoate. Over the 48-h observation period, the distribution of 211At- and 131I-labeled antibody were quite similar in tumor and normal tissues except stomach. These data were used to calculate human radiation doses for both intravenously and intrathecal administered 211At-labeled chimeric 81C6 using a quality factor of 5 for alpha-emissions.

3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells.

An analogue of meta-iodobenzylguanidine (MIBG) in which an aromatic hydrogen was replaced with fluorine has been found to possess many properties similar to those of the parent compound. Moreover, 4-fluoro-3-iodobenzylguanidine (FIBG) was retained in vitro by human neuroblastoma cells to a much greater extent than MIBG itself. Since alpha-emitters such as 211At could be valuable for the treatment of micrometastatic disease, an FIBG analogue in which the iodine atom is replaced by 211At would be of interest. In this study, we have evaluated the in vitro and in vivo properties of 3-[211At]astato-4-fluorobenzylguanidine ([211At]AFBG). The specific binding of [211At]AFBG to SK-N-SH human neuroblastoma cells remained fairly constant over 2- to 3-log activity range and was similar to that of [131I]MIBG. The uptake of [211At]AFBG by this cell line was reduced by desipramine, ouabain, 4 degrees C incubation, noradrenaline, unlabelled MIBG and FIBG, suggesting that its uptake is specifically mediated through an active uptake-1 mechanism. Over the 16 h period studied, the amount of [211At]AFBG retained was similar to that of [131I]FIBG, whereas the per cent of retained meta-[211At]astatobenzylguanidine ([211At]MABG) was considerably less than that of [131I]FIBG (53% vs 75%; P < 0.05). The IC50 values for the inhibition of uptake of [131I]MIBG, [211At]MABG, [125I]FIBG and [211At]AFBG by unlabelled MIBG were 209, 300, 407 and 661 nM respectively, suggesting that the affinities of these tracers for the noradrenaline transporter in SK-N-SH cells increase in that order. Compared with [211At]MABG, higher uptake of [211At]AFBG was seen in vivo in normal mouse target tissues such as heart and, to a certain extent, in adrenals. That the uptake of [211At]AFBG in these tissues was related to the uptake-1 mechanism was demonstrated by its reduction when mice were pretreated with desipramine. However, the stability of [211At]AFBG towards in vivo dehalogenation was less than that of [211At]MABG, as evidenced by the higher uptake of 211At in thyroid, spleen, lungs and stomach.

5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic agent undergoing DNA incorporation.

When labeled with the subcellular range Auger electron emitters 125I and 123I, the thymidine analogue 5-iodo-2'deoxyuridine (IUdR) is highly cytotoxic but only to cells going through S-phase during exposure to these radiopharmaceuticals. Since 211 At emits alpha-particles of high linear energy transfer, but with a range of a few cell diameters, an IUdR analogue labeled with 211At could markedly improve the homogeneity of tumor dose deposition. Herein we describe the synthesis of 5-[211 At]astato-2'-deoxyuridine ([211 At]AUdR) in 85-90% radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2'-deoxyuridine. In vitro studies using the human glioma cell line D-247 MG demonstrated that [211 At]AUdR was virtually identical to [131I]IUdr; both exhibited a linear increase in cell uptake with activity concentration, an inhibition of uptake by 10 micrometers IUdR, and the incorporation of about 50% of cell-bound activity into DNA. In a clonogenic assay, [211 At]AUdR exhibited a high cytotoxicity for D-247 MG cells, with a D(0) equivalent to less than 3 211At atoms/cell.

Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (alpha,2n)211 at reaction.

Astatine-211 is a 7.2 h half-life alpha-emitting radionuclide which has shown great promise for targeted radiotherapy. It is generally produced by cyclotron bombardment of bismuth metal targets with 28 MeV alpha-particles via the 209Bi(alpha,2n)211 At reaction. In order to provide 211At activity levels anticipated for clinical investigations, an internal target system has been designed and evaluated. The system has a grazing-angle configuration and leading- and trailing-edge monitors. Both aluminum and copper target backings were evaluated. With approx. 28 MeV alpha-particles, the 211At production efficiency was 41 +/- 7 MBq/microA.h, compared with 10.6 +/- 1.2 MBq/microA.h for an external target. Radionuclidic purity of 211At was high with no evidence of 210At.

Alpha-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 alpha-particle emitting radionuclide 211At were injected intraperitoneally in mice inoculated intraperitoneally 30 hr in advance with 10(6) 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 IgG kappa (211At-hIgG kappa), 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 211At-MDPP, and down to 25 kBq for 211At-hIgG kappa. There were no significant differences in survival between 211At-MDPP, 211At-hIgG kappa, 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-hIgG kappa (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 211At-TP-3 and 211At-hIgG kappa was still present intraperitoneally. In conclusion this study indicates that 211At-labeled MDPP and 211At-labeled IgG's may be efficient tools for treatment of intraperitoneal superficial tumor cells and malignant ascites.