Synthetic Strategies for the Preparation of Lipophilic MRI/GdBNCT Agents

BNCT (boron neutron capture therapy) is a binary radiation therapy for the treatment of cancer, based on the capture of thermal neutrons by 10B nuclei that have been selectively delivered to tumour cells.1 The neutron capture event results in the formation of excited 11B nuclei that undergo fission to yield highly energetic 4He2+ and 7Li3+ ions. Cell death is triggered by the release of these charged particles which create ionisation tracks along their trajectories, resulting in cellular damage. It has been estimated that approximately 10−30 µg of boron per gram of tumour mass is needed to attain an acceptable therapeutic advantage. Several functionalised carboranes have been employed to construct boron delivery vehicles for BNCT, because of their high content of boron and their stability in vivo. In recent years our research group has been working on the preparation of dual agents for BNCT/MRI applications. In these systems a carborane cage is linked to a lipophilic unit, in order to exploit LDLs as biological vectors, and a MRI probe. In vivo MR image acquisition showed that the amount of B taken up in the tumour region was above the threshold for successful NCT treatment.2 With the goal of improving the efficacy as theranostic agents (therapy + diagnostic), new compounds have been prepared and tested. In one case, a triazole unit was as a linker between the carborane cage, the MRI probe and the lipophilic unit (figure 1).3 The ability of the Gd complex of the synthesised ligand to form stable adduct with LDLs was evaluated and then MRI has been performed on tumour melanoma cells incubated in the presence of a Gd-complex/LDL imaging probe. In was demonstrated that the high amount of intracellular boron necessary to perform BNCT can be reached even in the presence of a relatively low-boron-containing LDL concentration. In order to exploit liposomes as biological vectors, a cholesterol moiety has also been introduced (Gd-B-AC01).4 An in vitro test on IGROV-1-cells demonstrated that this Gd-B-AC01 loaded liposomes are efficient carriers for the delivery of the MRI/BNCT probed to the tumour cells. The BNCT treatment of IGROV cells showed that the number of surviving cells was markedly smaller when the cells were irradiated after internalisation of the folate-targeted Gd-B-AC01/liposomes. Fig. 1. Example of MRI/BNCT dual agent where the MRI probe and the lipophilic unit are linked to the carborane cage via a triazole unit. In order to reduce the synthetic steps, a new strategy, based on the hydroboration reaction, has been elaborated. In this way the lipophilic unit will be linked to the carborane by a B-C bond instead of C-C, allowing the desired dual agent in only four passages to be obtained.