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

Larsen, Roy H.; Hoff, P.; Vergote, Ignace; Bruland, Øyvind S.; Aas, Magne; Vos, Laure De; Nustad, Kjell

doi:10.1006/gyno.1995.1093

Cited by 26 publications

(12 citation statements)

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“…In studies performed with 211 At bound to polystyrene microparticles, higher cure rates in mice with IP tumors were obtained than after treatment with β-emitting 32 P-colloid [12] . Interestingly, when the antitumor effect of the 211 At-microparticles was compared with unspecific 211 At-labeled antibody, similar survival but no clear dose-response relationship was observed [10] . This can indicate that the benefit of longer residence time in the peritoneal cavity with microparticles as carriers was not fully exploited with a short-lived nuclide like 211 At or that the distribution of the microparticles in the peritoneal cavity was not optimal.…”

Section: Discussionmentioning

confidence: 99%

“…IP therapy with α-emitters has previously been examined in murine models with two carrier types: nano- to microsized particles [9] , [10] , [11] , [12] and monoclonal antibodies [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] . With particles as carriers for radionuclides, it is possible to choose a size that facilitates a high retention of the particles in the peritoneal cavity [22] , [23] and thus contribute to the therapeutic radiation being delivered in the target location.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Westrøm

Bønsdorff

Bruland

et al. 2018

Translational Oncology

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BACKGROUND: Ovarian cancer patients with chemotherapy-resistant residual microscopic disease in the peritoneal cavity have a considerable need for new treatment options. Alpha-emitting radionuclides injected intraperitoneally may be an attractive therapeutic option in this situation as they are highly cytotoxic, while their short range in tissues can spare surrounding radiosensitive organs in the abdomen. Herein we evaluate the therapeutic efficacy of a novel α-emitting compound specifically designed for intracavitary radiation therapy. METHODS: The α-emitter 224Ra was absorbed on calcium carbonate microparticles. Immunodeficient, athymic nude mice with human ovarian cancer cells growing intraperitoneally were treated with different activity levels of 224Ra-microparticles. Tumor growth, survival, and tolerance of the treatment were assessed. Two tumor models based on the cell lines, ES-2 and SKOV3-luc, with different growth patterns were studied. RESULTS: In both models, intraperitoneal treatment with 224Ra-microparticles gave significant antitumor effect with either considerably reduced tumor volume or a survival benefit. An advantageous discovery was that only a few kilobecquerels per mouse were needed to yield therapeutic effects. The treatment was well tolerated up to a dose of 1000 kBq/kg with no signs of acute or subacute toxicity observed. CONCLUSIONS: Intraperitoneal α-therapy with 224Ra-microparticles demonstrated a significant potential for treatment of peritoneal micrometastases in ovarian carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Westrøm

Bønsdorff

Bruland

et al. 2018

Translational Oncology

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“…administration to mice inoculated with the K13 hybridoma cell line. 101 Biodistribution studies indicated that free 211 At -spread rapidly in the whole body, whereas the microsphere and the antibodies were mostly retained in the peritoneal cavity, highlighting a good stability. However, the authors concluded that the efficiency of the astatinated antibodies was superior to the microspheres due to a better diffusion in the peritoneal area.…”

Section: Astatination and Stability Of Biomolecules Of Interestmentioning

confidence: 98%

Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Guérard

Gestin

Brechbiel

2013

Cancer Biotherapy and Radiopharmaceuticals

105

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(211)At is a promising radionuclide for α-particle therapy of cancers. Its physical characteristics make this radionuclide particularly interesting to consider when bound to cancer-targeting biomolecules for the treatment of microscopic tumors. (211)At is produced by cyclotron irradiation of (209)Bi with α-particles accelerated at ~28 MeV and can be obtained in high radionuclidic purity after isolation from the target. Its chemistry resembles iodine, but there is also a tendency to behave as a metalloid. However, the chemical behavior of astatine has not yet been clearly established, primarily due to the lack of any stable isotopes of this element, which precludes the use of conventional analytical techniques for its characterization. There are also only a limited number of research centers that have been able to produce this element in sufficient amounts to carry out extensive investigations. Despite these difficulties, chemical reactions typically used with iodine can be performed, and a number of biomolecules of interest have been labeled with (211)At. However, most of these compounds exhibit unacceptable instability in vivo due to the weakness of the astatine-biomolecule bond. Nonetheless, several compounds have shown high potential for the treatment of cancers in vitro and in several animal models, thus providing a promising basis that has allowed initiation of the first two clinical studies.

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“…In a preliminary study performed in a murine ascites tumor model, significant prolongation in median survival was observed even at 211 At-labeled monodisperse polymer particles doses as low as 7 kBq (0.19 µCi) [40]. Although only a 20% cure rate was observed, it is difficult to ascertain the potential utility of this reagent because the maximum activity level investigated was only 500 kBq (13.5 µCi), considerably below the expected maximum tolerated dose of this labeled particulate.…”

Section: Astatine-211-labeled Particu-lates For Intracavity Applica-tmentioning

confidence: 98%

Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

Zalutsky

Vaidyanathan²

2000

CPD

170

102

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Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

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

Cited by 26 publications

References 0 publications

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

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

Cited by 26 publications

References 0 publications

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Production of [211At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy

Contact Info

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Production of [²¹¹At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy