No abstract available

No abstract available

[en] The heavy halogen ²¹¹At was first proposed for use in α-particle targeted radiotherapy more than 30 years ago and continues to be one of the most promising radionuclides for this purpose. Although its 7.2-h half life is not ideal for intravenously administered whole antibodies, it is compatible with the pharmacokinetics of antibody fragments, peptides, aptamers and organic molecules. Its diverse chemistry allows its incorporation into a wide array of targeting vehicles, relying on its chemical similarity to iodine to provide a useful point of departure. On the other hand, the relatively low carbon-astatine bond strength is challenging. In common with the other α-emitters being discussed at this symposium, lack of reliable availability is one of the biggest hurdles in the use of ²¹¹At for targeted radiotherapy. However, in the case of ²¹¹At, it is not a question of production cost or availability of target material, because ²¹¹At can be produced in reasonable yield from natural bismuth targets. Rather, the difficulty is the lack of cyclotrons equipped with the medium energy α-particle beams required for its production. If the infrastructure for producing ²¹¹At is to be improved to the stage where 211At-labeled radiopharmaceuticals can have a meaningful impact, several developments must occur. First, the ability to produce clinically relevant levels of ²¹¹At that can be shipped to remote locations in chemically tractable form must be demonstrated. Approaches under consideration include compensating for radiolysis-mediated effects and the consideration of alternative chemistries. Second, strategies for compensating for heterogeneities in dose deposition must be developed, hopefully in a way that is compatible with approval for human use. And third, it is essential that more clinical trials be performed with ²¹¹At-labeled therapeutics, particularly in settings of minimum residual disease where the radiobiological advantages of α-particles can be best exploited. Our own efforts in that regard will be to acquire the remaining data needed to initiate clinical evaluation of meta- [²¹¹At]astatobenzylguanidine and ²¹¹At-labeled trastuzumab in patients with neuroblastoma and breast cancer neoplastic meningitis, respectively. In conclusion, the major barrier in moving ²¹¹At-labeled targeted radiotherapeutics from appealing concept to practical treatment is the limited availability of the radionuclide. Hopefully, advances in radiochemistry and the results clinical trials at multiple institutions will provide a compelling rationale for the construction of more cyclotrons capable of producing ²¹¹At. (author)

[en] In this paper, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate(APB), a amidobisphophonate was synthesized and labeled with the α-emitter ²¹¹At by an indirect method using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate (SPC) as a bi-functional linker, and the conjugated amidobisphophonate (²¹¹At-SAPC-APB) was preliminarily evaluated in vitro and in vivo by comparison with free astatide (²¹¹At^-) and ^99mTc-MDP. 3-amino-1-hydroxypropylidene-1,1-bisphosphonate(APB) was prepared using β-alanine as the starting material. With SPC bi-functional linker, APB was conjugated with ²¹¹At in a labeling yield of 80-90% with radiochemical purity of more than 99%. The conjugated amidobisphophonate (²¹¹At-SAPC-APB) exhibited considerable stability in vitro, in that the radiochemical purity of ²¹¹At-SAPC-APB was still more than 98% in 0.1 mol/L PBS (pH 7.6) or in fetal calf serum, even stayed for 24 h at room temperature (RT). Biodistribution of ²¹¹At-SAPC-APB was investigated in NIH strain mice by I.V injection. The results showed that ²¹¹At-SAPC-APB could rapidly locate in shank, with the maximum uptake of 23.70 ± 2.29% I.D/g at 6 h, earlier than that of ^99mTc-MDP at 12 h, and stayed in the bone for long time. Moreover, ²¹¹At-SAPC-APB uptake in some key organs or tissues, especially in thyriod, stomach, lung and spleen, was much less than that of free astatide (²¹¹At^-), implying that ²¹¹At-SAPC-APB was constantly stable in vivo as well as in vitro. These results indicated that ²¹¹At-SAPC-APB will be a suitable candidate for the targeted radiotherapy of bone metastases and should be further investigated. (author)

[en] Alpha emitting radionuclides with medically relevant half-lives are interesting for treatment of tumors and other diseases because they deposit large amounts of energy close to the location of the radioisotope. Researchers at the Cyclotron Institute at Texas A&M University are developing a program to produce ²¹¹At, an alpha emitter with a medically relevant half-life. The properties of ²¹¹At make it a great candidate for targeted alpha therapy for cancer due to its short half-life (7.2 h). Astatine-211 has now been produced multiple times and reliability of this process is being improved.

[en] The determination of radiolysis products is an important field both for the basic understanding of the radiolysis process and for process development. The latter case mainly dealing with processes for handling radioactive wastes. There are several kinds of radiolysis processes that originate from the different kinds of radiation. Gamma rays and high-energy beta has a high ability to penetrate barriers while alpha irradiation in principle has to be performed with the radiation emitting nuclide inside the actual sample. This can be a problem since most laboratories able to identify radiolysis products cannot handle alpha contaminated samples. In this paper we suggest the use of ²¹¹At as internal alpha emitting radionuclide. Due to its short half-life and decay to more or less stable daughters the radiolysis products may be examined using normal equipment without causing contamination.

No abstract available

[en] Full text of publication follows. Targeted alpha therapy (TAT) is a treatment modality that has gained interest for adjuvant treatment of occult disseminated cancer. Among the limited number of possible α-emitting radionuclides At"2"1"1 (Astatine-211) has been frequently recognized as one of the most promising candidate. The nuclide has been investigated in a number of preclinical studies, utilizing the free halide and different astatinated tumor specific carrier vectors. The most common vector has been monoclonal antibodies directed against a variety of different malignancies i.e. in radioimmunotherapy (RIT) applications. Promising preclinical results have been obtained, and two of the preclinical RIT studies have been translated into phase I studies, one study on malignant glioma at Duke University, USA, and one study on ovarian carcinoma at the University of Gothenburg, Sweden [Refs. 1,2]. However, the applications of radiolabelled antibodies in cancer therapy are limited by slow distribution and slow clearance rates, resulting in slow accumulation at the tumour sites. Therefore, the half-life of At"2"1"1 is generally too short for conventional RIT except for a few special applications such as the above mentioned intracavitary treatments. In order to circumvent the unfavourable pharmacokinetics of radiolabelled antibodies, different ways of improving the distribution of the radioactivity have been suggested, employing various pre-targeting techniques. With this type of technique modified antibodies are administered for pre-binding to the tumour antigens. A sufficient time is introduced, to allow non-bound antibodies to be cleared from the circulating system, or a clearing agent is administered to enhance the clearance rate before injecting the labelled effector molecule. The effector molecule recognizes a tag on the antibody and due to the small size of the effector molecule as compared to labelled antibodies, it will localize the target more rapidly and the non-bound fraction will be cleared more efficiently, thus increasing tumour uptake and lowering the dose to normal tissue. One of the main challenges for putting RIT and PRIT with At"2"1"1 into practice is the radiopharmaceutical chemistry. For example, there are a limited number of cyclotron facilities around the world capable of producing the nuclide and at each cyclotron there is a limited production capacity. Furthermore, although progress in the labelling chemistry there are still further improvement warranted [Ref. 3]. Except for radionuclide availability and labeling chemistry, the future of targeted α-therapy with At"2"1"1 also lies very much on optimal vectors and with the administration model. These hurdles need to be overcome if preclinical research is to be translated into clinical practices. References: 1] Zalutsky et al. JNM 2008; 2] Anderson et al. Clin Can Res. 2009; 3] Lindegren et al. JNM 2008. (authors)

[en] We reported recently the induction of selective iodide uptake in prostate cancer cells (LNCaP) by prostate-specific antigen (PSA) promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of ¹³¹I. In the current study, we studied the potential of the high-energy alpha-emitter ²¹¹At, also transported by NIS, as an alternative radionuclide after NIS gene transfer in tumors with limited therapeutic efficacy of ¹³¹I due to rapid iodide efflux. We investigated uptake and therapeutic efficacy of ²¹¹At in LNCaP cells stably expressing NIS under the control of the PSA promoter (NP-1) in vitro and in vivo. NP-1 cells concentrated ²¹¹At in a perchlorate-sensitive manner, which allowed a dramatic therapeutic effect in vitro. After intrapertoneal injection of ²¹¹At (1 MBq), NP-1 tumors accumulated approximately 16% ID/g ²¹¹At (effective half-life 4.6 h), which resulted in a tumor-absorbed dose of 1,580 ± 345 mGy/MBq and a significant tumor volume reduction of up to 82 ± 19%, while control tumors continued their growth exponentially. A significant therapeutic effect of ²¹¹At has been demonstrated in prostate cancer after PSA promoter-directed NIS gene transfer in vitro and in vivo suggesting a potential role for ²¹¹At as an attractive alternative radioisotope for NIS-targeted radionuclide therapy, in particular in smaller tumors with limited radionuclide retention time. (orig.)

[en] Full text of publication follows. Collaborations are currently ongoing between the high-power particle accelerator (cyclotron) ARRONAX located at Nantes, Cancer Research Centre Nantes-Angers, SUBATECH and the synthetic chemistry group of Prof. David Deniaud (CEISAM). Some projects aim at the development of new chelating agents of radionuclides for nuclear medicine applications (radioimmunotherapy or cancer imaging). This project aims at the design of new radiopharmaceuticals of Astatine 211 for applications in alpha particle targeted radiotherapy. Astatine 211, an artificial halogen, has physical properties that make it interesting for applications in cancer treatment: the radionuclide has a half-life of 7.2 h, it decays via emission of a high energy alpha particle without producing toxic daughter isotopes. Furthermore, the short path-length of emitted alpha particles (50-80 μm) and the large energy deposit over a small distance of a few cells diameters allow for the irradiation of only a few cells (micrometastases) with a very high cytotoxicity, causing only limited damage to surrounding normal tissues (Ref. 1). To be used in cancer therapy, "2"1"1At has to be delivered specifically at the tumour cells. The direct coupling of "2"1"1At to antibodies that are specific of antigens present at the surface of the tumour cells form radio-immuno-conjugates that are prone to in vivo de-astatination: such carriers are not suitable for therapy. To minimise in vivo de-astatination, one strategy under investigation is to bind "2"1"1At to polyhedral boron clusters attached via linkers to antibodies targeting specific cancer cells (Ref. 2). Boron cages are inorganic tri-dimension aromatic structures that are not recognised by enzymes which improves the in vivo stability (Ref. 3). Boron-halogen bonds are stronger than carbon-halogen bonds which should also significantly help to decrease in vivo de-astatination. Our synthetic results aiming at the identification of suitable closo-boranes clusters for such radiotherapy applications with a specific internalizing antibody will be presented. We get the following scheme: At"2"1"1 -- Boron Cage -- Linkers -- mAb. References: 1] D.S. Wilbur, Nature Chemistry, 2013, 5, 246; 2] D.S. Wilbur, M.K. Chyan, H. Nakamae, Y. Chen, D.K. Hamlin, E.B. Santos, B.T. Kornblit, B.M. Sandmaier, Bioconjugate Chem., 2012, 23, 409; 3] F. Issa, M. Kassiou, L.M. Rendina, Chem. Rev., 2011, 111, 5701. (authors)