Towards new radiopharmaceuticals of Astatine 211 containing Boron clusters for radioimmunotherapy of micro-metastatic diseases?

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, ²¹¹At has to be delivered specifically at the tumour cells. The direct coupling of ²¹¹At 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 ²¹¹At 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: At²¹¹ -- 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)