[en] 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

[en] The bone-seeking, alpha-particle emitting radiopharmaceutical Alpharadin, 223RaCl2 (t1/2 = 11.4 days) is under clinical development as a novel treatment for skeletal metastases from breast and prostate cancer. This paper summarizes the current status of preclinical and clinical research on 223RaCl2. Potential advantages of 223Ra to that of external beam irradiation or registered beta-emitting bone-seekers are discussed. Published data of 223Ra dosimetry in mice and a therapeutic study in a skeletal metastases model in nude rats have indicated significant therapeutic potential of bone-seeking alpha-emitters. This paper provides short-term and long-term results from the first clinical single dosage trial. We present data from a repeated dosage study of five consecutive injections of 50 kBq/kg bodyweight, once every third week, or two injections of 125 kBq/kg bodyweight, six weeks apart. Furthermore, preliminary results are given for a randomized phase II trial involving 64 patients with hormone-refractory prostate cancer and painful skeletal metastases who received four monthly injections of 223Ra or saline as an adjuvant to external beam radiotherapy. Also presented are preliminary dose estimates for 223Ra in humans. Results indicate that repeated dosing is feasible and that opportunities are available for combined treatment strategies

[en] The α-particle-emitting radionuclide ²²³Ra (t_1/2=11.4 d) is of interest for use in targeted radionuclide therapy. In order to provide radium-labeled monoclonal antibodies, the development of a chelator binding radium in a stable fashion is required. As a part of the search for potentially useful radium chelators, the relative stability of ²²³Ra-chelates with linear and cyclic chelating agents was evaluated by means of competition extraction experiments

[en] 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-[²¹¹ At]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 α-emissions

[en] The radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions--which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: (1) cationic 223Ra as dissolved RaCl2, and (2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similarities to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from late-stage breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor-to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent

[en] 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 28 MeV 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

[en] The bone-seeking property of and the potential to irradiate red marrow by the alpha-particle emitter Ra-223 (t1/2 = 11.43 d) were compared to those of the beta-emitter Sr-89 (t1/2 = 50.53 d). Methods: The biodistributions of Ra-223 and Sr-89 were studied in mice. Tissue uptakes were determined at 1 h, 6 h, 1 d, 3 d, and 14 d after intravenous administration. The potential redistribution of progeny from Ra-223 located in bone was investigated. Radiation absorbed doses were calculated for soft tissues and bone. Doses were also estimated for marrow-containing cavities assuming spheric geometries. Results: We found that both Sr-89 and Ra-223 selectively concentrated on bone surfaces relative to soft tissues. The measured bone uptake of Ra-223 was slightly higher than that of Sr-89. At the 24 h time-point, the femur uptake of Ra-223 was 40.1% of the administered activity per gram tissue. The uptake in spleen and most other soft tissues was higher for Ra-223 than for Sr-89. We observed rapid clearance of Ra-223 from soft tissues within the first 24 hours, but the bone surface uptake of Ra-223 increased with time up to 24 h. Among the soft tissues, the spleen had the greatest accumulation and retention of Ra-223. The femur-to-spleen ratio increased with time, from 6.4 at 6 h to 23.7 at 3 days after injections. We found little redistribution of Ra-223 daughter products away from bone (about 2% at 6 h and less than 1% detectable at 3 d). Estimates of dose to marrow-containing cavities showed that the Ra-223 alpha-emitter might have a marrow-sparing advantage compared to beta-emitters due to high linear-energy-transfer and short alpha range targeting osteoid surfaces. The alpha-emitters irradiate a smaller fraction of the marrow-containing volumes--sparing marrow and enhancing survival of marrow cells. At the same time, the bone surfaces receives a therapeutically effective radiation dose. Conclusion: The results of this study indicate that Ra-223 is a promising candidate for high linear-energy-transfer alpha-particle irradiation of cancer cells on bone surfaces. Radium-223 can, together with its daughter radionuclides, deliver an intense and highly localized field of radiation to bone surfaces with substantially less irradiation of healthy bone marrow dose compared to standard, bone-seeking beta-emitters such as Sr-89

[en] 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

[en] 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

[en] Purpose: The antitenascin human/mouse chimeric monoclonal antibody labeled with the α-particle-emitting radionuclide ²¹¹At is of interest as an endo radiotherapeutic 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 non thyroid 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