<sup>211</sup>At‐labelling of polymer particles for radiotherapy: Synthesis, purification and stability

Larsen, Roy H.; Hassfjell, Sindre P.; Hoff, P.; Alstad, J.; Olsen, Eivind; Vergote, Ignace; Vos, Laure N. De; Bjørgum, Jon; Nustad, Kjell

doi:10.1002/jlcr.2580331012

Cited by 22 publications

(7 citation statements)

References 10 publications

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“…After separation from the bismuth target (Larsen et al, 1993), the astatine was coupled to the MAb or BSA using the ATE method (Zalutsky & Narula, 1987;Garg et al, 1989). The procedures for astatine labelling of MAbs have been described in detail elsewhere .…”

Section: Cell Linesmentioning

confidence: 99%

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

Larsen

Bruland²,

Hoff³

et al. 1994

Br J Cancer

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Summary Microcolonies were obtained by culturing cells of two human osteosarcoma lines (OHS and KPDX) and one human melanoma line (WIX-c) for either 24 or 72 h. The microcolonies were treated with either a-particle radiation emitted by the 2"'At-labelled monoclonal antibody (MAb) Compounds labelled with the a-particle emitter 2"'At have for some time been preclinically investigated as a means for irradiation of tumour cells (Bloomer et al., 1981;Brown et al., 1981;Vaughan et al., 1981Vaughan et al., , 1982Harrison & Royle, 1987;Link et al., 1989). Although therapeutic effects have been achieved with compartmentally delivered non-specific 2"'At preparations in murine models (Bloomer et al., 1984;Vergote et al., 1992), the use of 2"'At-labelled compounds with some degree of selective tumour uptake seems to be the most promising strategy (Humm, 1987;Humm & Chin, 1993). The therapeutic potential of a-emitters is increased when they are coupled to molecules with high tumour affinity because of the short range and high ionisation density of a-particles (Brown, 1986;Kozak et al., 1986;Kurtzman et al., 1988;Macklis et al., 1989).We have recently studied the cytotoxicity of 2"At-TP-3 monoclonal antibody (MAb) on single-cell suspensions of three human osteosarcoma cell lines (OHS, SAOS and KPDX) (Larsen et al., 1994). The study showed that the sensitivity to 2"1At-TP-3 treatment was governed by cellular properties other than those governing sensitivity to treatment with external beam X-rays. The cellular property most important for sensitivity to 21 At-TP-3 was the antigen density. The cell inactivation was found to increase substantially with increasing specific activity of the 21 At-TP-3 preparation.At high specific activities, the cytotoxic effect of 2"1At-TP-3 was significantly higher than that of non-specific 21 Atlab.elled bovine serum albumin (BSA). It was concluded that 21 At-TP-3 of high specific activity may have the potential to give clinically favourable therapeutic ratios in the treatment of osteosarcoma.The clinical conditions for many types of cancer are normally very different from the conditions in the single-cell suspension model. Osteosarcoma, for instance, has a strong tendency to metastasise by cells being trapped in the bone marrow sinusoids and lung capillaries. Cells in microcolonies infiltrating or growing adjacent to normal tissue will have binding kinetic conditions different from free-floating single cells. Steric hindrance from adjacent cells may reduce the number of antigens available for circulating MAbs and, hence, reduce the potential of radioimmunotherapy (RIT).On the other hand, radiation cross-fire from radiolabelled antibody molecules bound to antigens of neighbouring cells may enhance the efficacy of RIT against tumour cell colonies.In the present paper we have extended our in vitro investigation of a-particle RIT from the single-cell suspension model to a surface-deposited microcolony model. A surfacedeposited microcolony model was chosen rather than a multicellular spheroid m...

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Section: Cell Linesmentioning

confidence: 99%

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

Larsen

Bruland²,

Hoff³

et al. 1994

Br J Cancer

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“…Co-precipitation of 211 At with silver iodide yielded a colloid that retained 95% activity in particulate form after a 24-hr incubation with 50% fetal calf serum [38]. Larsen et al [39] have labeled aminated 1.8-µm diameter polymer particles with 211 At and did not observe any loss of 211 At from the particles after a As shown in Fig. 5, the synthesis of 6-[ 211 At]astato-MNDP was originally performed using a four step procedure but is now done in a single step by solid state heterogenous isotopic exchange in vacuo at 170 o C [43].…”

Section: Astatine-211-labeled Naphtho-quinone Derivativesmentioning

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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“…Although devoid of active targeting properties, nanoparticles and larger particles have been investigated with potential applications for locoregional administration. Larsen et al 100 prepared 211 Atmicrospheres by conjugation of aminated polymer particles to SAB. The resulting particles with a size of 1.8 lm were stable in various media in vitro.…”

Section: Astatination and Stability Of Biomolecules Of Interestmentioning

confidence: 99%

“…The resulting particles with a size of 1.8 lm were stable in various media in vitro. 100 They were compared to free 211 Atand astatinated antibodies by i.p. administration to mice inoculated with the K13 hybridoma cell line.…”

Section: Astatination and Stability Of Biomolecules Of Interestmentioning

confidence: 99%

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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²¹¹At‐labelling of polymer particles for radiotherapy: Synthesis, purification and stability

Cited by 22 publications

References 10 publications

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

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

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

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211At‐labelling of polymer particles for radiotherapy: Synthesis, purification and stability

Cited by 22 publications

References 10 publications

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody

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

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

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Product

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²¹¹At‐labelling of polymer particles for radiotherapy: Synthesis, purification and stability

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