Advancing novel strategies for the management of triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited response to conventional treatments. This thesis investigates three strategies that combine nanoparticles (NPs), ionizing radiation, and photonics to improve TNBC treatment. The first study evaluated the radiosensitizing potential of chitosan-based nanoparticles encapsulated with a nitric oxide donor (GSNO-CSNPs), combined with radiotherapy (RT) in a murine TNBC model. In vitro assays showed that the combination of GSNO-CSNPs at the IC30 dose with 6 Gy RT significantly increased cell death, possibly due to enhanced oxidative stress. In vivo, the combination of GSNO-CSNPs at the IC60 dose with 12 Gy RT significantly reduced tumor growth and pulmonary metastasis. The second study focused on brachytherapy (BT) using Iodine-125 seeds for localized treatment of TNBC in mice. BT significantly delayed tumor growth, and Monte Carlo simulations were used to estimate the dose absorbed by the tumor and vital organs over 15 days. We demonstrated that different gold NP geometries led to the same dose enhancement, with no significant variations. However, when simulating NP diffusion in the tissue over 4 h, we observed a reduction in the dose delivered to the target, as a result of NP dispersion within the tumor. In the third study, a tumor-on-a-chip model was developed to evaluate photothermal therapy (NP-PTT) mediated by gold nanorods exposed to a NIR laser. Spheroids from MCF7 and MDA-MB-231 cell lines, cultured in a 3D microfluidic environment, were subjected to NP-PTT, resulting in significant and comparable cell death in both cell lines. Additionally, a subtle, dose-dependent increase in the vimentin/E-cadherin ratio was observed in MCF7 spheroids, a possible epithelial-to-mesenchymal transition, which was not detected in the MDA-MB-231 cell line. Our results demonstrate that the combination of nanotechnology, radiation, and photonics can be explored at different scales to enhance TNBC therapies, optimize treatment delivery, enable the analysis of subtle cellular responses, and contribute to the development of more effective and personalized therapeutic approaches.