Radiopharmaceutcials radiolabelled with ¹⁸⁸Re as potential therapeutic tools for hepatocellular carcinoma targeting

Hepatocellular carcinoma (HCC), is the second most common cause of death from cancer worldwide (745 000 deaths). Since 2008, HCC is the cancer with the highest mortality rate (0.95).^[1] Nowadays, the only systemic treatment that has demonstrated a real benefit in advanced HCC is Sorafenib, but it remains associated with many side effects and this therapy is still very expensive. So, it is desirable to offer a treatment more efficient, and cheaper.

Many studies showed the overexpression in tumor tissue, and especially in HCC cases, of somatostatin receptors in contrast to healthy cells. ^{[2, 3]} That’s why, these kind of receptors are interesting for tumor targeting, either for imaging or for therapy. Indeed, selective localization or destruction of cancer cells by means of such radiolabelled bioconjugates is a simple and attractive concept, based on the use of the recognition properties of biomolecules towards tumour cells (magic bullet concept).^[4] The challenge is to develop radiotracers, so-called radiopharmaceuticals, which consist in a three-parts system including a biomolecule, a bifunctional chelating agent (BCA) and a radioactive isotope which delivers γ or β^- emission. To be efficient, this system must be stable in vivo in order to image and/or irradiate selectively the targeted tumour mass. Consequently, our challenge is to develop a targeting radiopharmaceutical with Rhenium-188 as destructive part, a tripodal N₂O bifunctional chelator and as biovector, a synthetic somatostatin analogue.

In this communication, we reported our first results related to the development of a targeting radiopharmaceutical including: (i) the synthesis of original tripodal N₂O BCAs based on a triazolyl moiety, these chelators being synthesised via a click chemistry approach ^[5], (ii) a complete structural study of corresponding non-radioactive tricarbonylrhenium complexes (iii) the first trials of coupling and of ¹⁸⁸Re-labelling of the tripodal ligand (proof of concept).

References:

^[1]            J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D.M. Parkin, D. Forman, F. Bray, Int. J. Cancer, 2014, 136, E359–E386

^[2]               J. C. Reubi, A. Zimmermann, S. Jonas, B. Waser, P. Neuhaus, U. Läderach, B. Widenmann, Gut, 1999, 45, 766-774

^[3]            H. Reynaert, K. Rombouts, A. Vandermonde, D. Urbain, U. Kumar, P. Bioulac-Sage, M. Pinzani, J. Rosenbaum, A. Geerts, Gut, 2004, 53, 1180-1189

^[4]            C.F. Ramogida, C. Orvig, Chem. Commun., 2013, 49, 4720-4739

^[5]            S. Guizani, N. Malek-Saied, C. Picard, E. Benoist, M. Saidi, J. Label. Compd Radiopharm., 2014, 57, 158-163.