Proton Beam Irradiation Affects the Way Breast Cancer Cells Take Up Nanoparticles in Relation to the Stiffness of Their Microenvironment

High-frequency proton therapy shows promise for breast cancer (BC) treatment. We previously showed that BC cells’ metastatic potential (MP) correlates with their nanoparticle (NP) uptake efficiency. MP is known to be associated with microenvironment stiffness and radiosensitivity. Here, proton beam-irradiated MCF-7 and MDA-MB-231 cells were assessed for NP uptake efficiency under stiff (plastic) or soft (fibrin gel) conditions. In a stiff microenvironment, control MDA-MB-231 cells internalized 1.35-fold more NPs than MCF-7 (p < 0.0017), with comparably low uptake in soft conditions. After proton beam irradiation at a dose of 6 Gy, in stiff conditions, MDA-MB-231 cells showed a 1.6-fold increase in NP internalization compared to non-treated MDA-MB-231 (p < 0.0001), while MCF-7 cells showed no change, leading to an overall 1.86-fold difference between proton-treated MDA-MB-231 and MCF-7 cells (p < 0.0001). In soft conditions, irradiated MDA-MB-231 retained a 1.47-fold higher uptake of NPs than MCF-7 cells (p < 0.0172), but this value was 1.7-fold lower (p < 0.0001) compared to non-irradiated MDA-MB-231 cells on stiff plastic. Hence, therapeutic strategies combining proton irradiation with targeting tumor microenvironment softening may reduce post-irradiation metastasis risk.