Project Funding Details

Lung cancer is a disseminated tumour, often inoperable, with limited efficacy of conventional radiotherapy due to the presence of radiosensitive tissues limiting the delivered maximum dose. Other factors that contribute to lower cure rates include: late diagnosis, metastatic potential, and chemoresistance. Therefore, the development of new multi-target therapeutic protocols is of great interest to improve treatment outcomes. Here, we propose treating lung cancer with properly designed Boron containing, Epidermal Growth Factor Receptor (EGFR) and CAIX inhibitors for a synergic merging of enhanced chemio-therapy with Neutron Capture Therapy (NCT), a binary hadrontherapy that can selectively target tumours at the cellular level. NCT is particularly effective in treating diffuse tumors affecting vital organs. This approach is based on the local and well controlled generation of alpha-particles on demand, thanks to the nuclear reaction between non-radioactive 10B and thermal neutrons, thus reducing the side effects of a non-specific distribution of alpha-emitting nuclides. The aim of this project is to combine EGFR and CAIX inhibition with BNCT using functionalized carboranes (cluster of 10B atoms) conjugated to a Gd-complex. Incorporating an MRI probe into the NCT agent, it is possible to assess the concentration of 10B in the tumor region, thus offering the possibility of personalized therapy. In addition, the non-radioactive 157Gd can also react with neutrons to produce high LET Auger-electrons, further enhancing the therapeutic power. The first phase will involve the synthesis and testing of new derivatives on cellular models. The second phase will address the in vivo testing of the uptake performance of 10B and 157Gd. Cell uptake will be assessed by MRI/ICP-MS. The best performing compounds will be selected for in vivo studies. Cell and animal irradiation will take place at the nuclear reactor of Pavia University. The progression of tumors after treatment will be monitored using MRI. We expect that the synergy created by the inhibition of selected epitops, together with the generation of alpha-particles and/or Auger-electrons at the target site, may induce a complete tumor regression avoiding recurrence. In view of the clinical translation, the proposed strategy will be applied by delivering nanoparticles loaded with clinically approved boron-carriers and MRI contrast agents. The acquisition of the MRI readout will allow to determine the optimal neutron irradiation time and a precise calculation of the delivered dose. The possibility to offer a more precise treatment option for patients with no perspectives of survival, will improve their quality of life and overall conditions of both patients and parents. Actually, BNCT only requires one, maximum two, irradiation sessions Another benefit is the adoption of a PRE-targeting technique, which involves injecting a non-radioactive, non-toxic chemical that will only be triggered after accumulating in the pathological site. Currently, BNCT has only been implemented in centers having access to research nuclear reactors. Actually, with high-current proton accelerators development, suitable neutron beams can now be produced and installed in hospitals. Some accelerator are now operative, and one will soon be installed at The National Hadron Therapy Oncological Center (CNAO) in Pavia.