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. 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.1 An important task relies on the possibility of delivery high payloads of 10B at the target sites and polynuclear boron derivatives are potential candidates for BNCT applications. 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 (AT101).2 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.3 With the goal of achieving an effective MRI/GdBNCT agent in a relatively few synthetic passages in mind, we have recently applied the Huisgen reaction carried out in heterogeneous conditions to the suitable substituted carborane cage. MRI images performed on tumour melanoma cells incubated in the presence of the Gd/B dual probe have demonstrated that the high amount of intracellular B necessary to perform BNCT can be reached using a relatively low B containing labelled LDL concentration.