Fe/57Fe-Metallacarboranes with Radiosensitizing Potential in Breast Cancer Cell Models: Comparative Study Between High- (60Co) and Low-Energy (57Co) Gamma Radiation Sources

<b>Background:</b> Radiosensitizers can be used to enhance tumor response and mitigate toxicity in healthy tissues during radiation therapy. This study investigates the radiosensitizing potential of the metallacarborane Fe/⁵⁷Fe-ferrabisdicarbollide in SK-BR-3 and MDA-MB-231 breast cancer cells, using two distinct gamma-photon sources: high-dose ⁶⁰Co (2.08 Gy) and low-dose ⁵⁷Co (37.55 mGy, ⁵⁷Fe Mössbauer effect). <b>Methods:</b> We evaluated cell viability and survival in 2D monolayer and 3D spheroid cultures, as well as the mechanism of cell death (ROS production, apoptosis or necrosis). Computational dosimetry was used to calculate the average absorbed dose. <b>Results:</b> In 2D models, both radiation sources induced reduced viability and increased ROS, with distinct cell death patterns dependent on the source (apoptosis or necrosis). Comparing 2D and 3D MDA-MB-231 models revealed that spheroid survival was significantly more impaired. The low-dose ⁵⁷Co source caused a significant radiosensitization in MDA-MB-231 spheroids, dramatically impacting viability and survival. This effect is attributed to the Mössbauer effect, where the resonant absorption of 14.41 keV radiation by ⁵⁷Fe leads to a massive, localized dose enhancement. The subsequent cascade of Auger and conversion electrons (local high LET) caused significantly greater cellular damage than sparse photon radiation. <b>Conclusions:</b> Fe/⁵⁷Fe-ferrabisdicarbollide demonstrates a potent radiosensitizing effect depending on the cell model and the radiation source used. Crucially, the observed radiosensitization allows for the development of a new, more efficient cancer radiotherapy approach that can achieve therapeutic efficacy using a significantly lower radiation dose to the patient. This paves the way for safer and better-tolerated cancer treatments.