Mesothelioma is a malignant neoplasm of mesothelial cells primarily caused by asbestos exposure and is highly aggressive. A multi-therapeutic approach is essential to improve treatment outcomes and prevent recurrence. Boron/Gadolinium Neutron Capture Therapy (B/Gd-NCT), combined with Carbonic Anhydrase IX (CA) inhibition, offers a promising strategy. NCT is a binary radiotherapy using thermal neutron capture by nuclides (mainly 10B and 157Gd) to target malignant tumors, aiming to destroy cancer cells while sparing nearby healthy tissue. Moreover, the use of Gd containing compounds enhances treatment by allowing monitoring through MRI.

2 types of compounds were synthesized and evaluated as 10B and 157Gd delivery agents to perform at the same time NCT and CA inhibition: 1-Boronated derivatives (CA-USF) containing a carborane cage conjugated with sulfamido and ureido groups. 2- Boronated derivatives (Gd-CA-SF) conjugated with sulfamido and a Gadolinium complex. BNCT and B/Gd-NCT experiments conducted on AB22 murine mesothelioma cells. Phantom imaging and uptake assessments were performed by incubating AB22 and Met-5A (normal mesothelium cell line) with Gd-CA-SF. In vivo experiments were then carried out using CA-USFs.

In vitro studies demonstrated that CA-USFs exhibited stronger CA inhibition than Acetazolamide. BNCT experiments on AB22 cells incubated with CA-USFs showed significant proliferation inhibition, with a complete suppression observed 20 days post-neutron irradiation. In vivo experiments showed a significant tumor reduction in mice treated with 10B-CA-USFs, especially with BNCT and CA IX inhibition. The uptake of Gd-CA-SF by AB22 cells was higher than that of Met-5A cells, consistently with the results of phantom imaging, thus demonstrating the selectivity of the system. In vitro B/Gd-NCT results showed that combining the effects of 157Gd and 10B with CA-SF, followed by irradiation, achieved the lowest proliferation rate in AB22 cells.

This study highlights the potential of combining BNCT with CA inhibition for mesothelioma treatment. CA-USFs showed strong CA inhibition, enhancing BNCT efficacy and completely suppressing AB22 cell proliferation in vitro while significantly reducing tumors in vivo. The selective uptake of Gd-CA-SF by AB22 cells, confirmed by phantom imaging, underscores the precision of this approach. The synergy of 157Gd, 10B, and CA inhibition achieved the lowest proliferation rates, demonstrating its therapeutic promise.