Novel carborane containing compounds for a synergic antitumoural effect of Carbonic Anhydrase Inhibition and Boron Neutron Capture Therapy for the mesothelioma treatment.

Carbonic Anhydrase IX (CAIX) is an indispensable enzyme which is overexpressed in various cancer cells, including mesothelioma and breast cancer. Therefore, the inhibition of this enzyme holds significant potential to enhance therapeutic interventions in these specific cancer types, particularly when employed in conjunction with other treatments. Among different therapeutic approaches, Boron Neutron Capture Therapy (BNCT), is a binary chemio- radiotherapeutic approach combining low energy neutron irradiation with the presence of boron-containing compounds in the target cells. Neutrons are captured by nonradioactive isotope 10 B that disintegrates into alpha particles and lithium nuclei that cause non reparable damage to the cell where they were generated, sparing the surrounding ones, potentially healthy. The primary objective of this study was to address this research by formulating and subsequently comparing a series of sulfonamido-functionalized carborane compounds, namely CA-SF, CA-USF, F-CA-USF, and No2-CA-USF (referred to as CA-SF,4a, 4b, and 4c respectively). These synthesized compounds were strategically designed to serve a dual purpose: firstly, as inhibitors of CAIX, and secondly, as agents for the targeted delivery of boron. Such multifunctionality underscores their potential as valuable tools for advancing therapeutic strategies in the context of cancer treatment. The synergistic cytotoxic effects induced by enzymatic inhibition and neutron irradiation were assessed in vitro using ZL34 and AB22 cancer cells. Subsequently, an in vivo model was established by subcutaneously injecting AB22 cells into Balb/c mice. No2/F derivative carborane compounds were administered as inclusion complexes with a β-cyclodextrin oligomer. The mice were divided into two groups. The first group underwent neutron irradiation, while the second group did not receive any irradiation. The results obtained from this study are highly promising. Tumor growth was significantly lower in comparison to the control group. Additionally, mice that received only the compound without irradiation also exhibited reduced tumor growth. These findings highlight the potential of the combined treatment approach involving enzymatic inhibition, neutron irradiation, and the administration of No2/F derivative carborane compounds. The results suggest a marked inhibitory effect on tumor growth, both in vitro and in vivo.