Unravelling physical and radiobiological effects of proton boron fusion reaction with anionic metallacarboranes ([o-COSAN]) in breast cancer cells.

Background: Protons, which are considered low-LET (Linear Energy Transfer) radiation, have an average RBE (relative biological effectiveness) of 1.1, with a range from 0.7 to 1.6. Thus, increasing biological effectiveness is of high interest in radiation oncology, and one way to enhance this is by using radiosensitizers. The present work investigates the effectiveness of the proton boron fusion reaction (PBFR) at the cellular level, using the sodium salt of metallacarborane [3,3'-Co(C2B9H11)2] (Na[o-COSAN]) as the boron source, aiming to explore the potential of this type of boron clusters as a radiosensitizer for proton therapy. Therefore, the main goal was to test the hypothesis that loading the cells with boron will favour the PBFR at energies close to the Bragg peak. This would enhance the radiation-induced biological effects through the production of alpha-particles.

Results: MDA-MB-231 breast cancer cells were used. Nuclear microscopy assessed [o-COSAN] uptake and distribution in single cells, while biodistribution was studied in tumor-bearing Balb/cSlc-nu/nu mice (MDA-MB-231 xenograft), with boron accumulation in target organs and tumor measured by ICP-OES. The cells were irradiated with a proton beam tuned to reach the PBFR resonance energy of 675 keV at the cell layer. DNA damage was assessed with the g-H2AX assay and cell survival with the clonogenic assay. Beam parameters and dose calibration curves using radiochromic films validated Monte Carlo dosimetry simulations. As expected, we observed higher biological damage in irradiated cells and the presence of [o-COSAN] potentiated the damage. These results translate into a lower cellular viability, indicating that DNA damage imposed colonies smaller than their non-irradiated counterparts. This suggests that these damages either took longer time to be repaired or made the cells undergo less efficient survival mechanisms.

Conclusions: The radiosensitizing effect of [o-COSAN] by strategic cellular B placement and proton irradiation intensifies the DNA damage, making the nucleus particularly susceptible and thus increasing the destructive capability of alpha-particles, generated in the nuclear fusion reaction, which may lead to increased cell mortality.