Multifunctional nanocarriers loading three orthogonal therapeutic agents enabling photo- and chemotherapy in hypoxic conditions

Triple-Negative Breast Cancer (TNBC) is an aggressive subtype of tumor often resulting lethal for patients and lacking an FDA-approved specific therapy. Chemotherapeutic agents, i.e. taxanes, are the first-line treatment for TNBC. Despite their efficacy, these drugs are virtually insoluble in water, thus requiring ad hoc formulations. Nowadays, photodynamic therapy (PDT) is receiving increasing attention for the treatment of solid tumors, including TNBC. PDT is based on a photosensitizer (PS) able to adsorb light in the red-NIR, skin-permeable portion of the spectrum. Upon irradiation, the PS interacts with the surrounding molecular oxygen to free reactive oxygen species (ROS), mainly singlet oxygen (1O2), able to trigger a cascade of processes eventually killing cancer cells. Yet, solid cancer cells like TNBC often suffer from tissue hypoxia, a condition causing an inadequate supply of O2, ultimately resulting in reduced PDT efficacy and induced resistance to taxanes. Our project aims to build a nanotechnological carrier able to combine three therapeutic routes in one synergistic platform. A biocompatible cyclodextrin-based polymer forming nanoparticles (NPs) in the range of 10-50 nm will be non-covalently loaded with a taxane, protecting it from degradation and enabling the in situ release of the drug. A promising PS, i.e. Chlorin e6, will be co-loaded into the NPs in order to allow effective PDT. Newly synthesized oxygen releasing agents (ORAs) based on aromatic endoperoxide bridges will be embedded in the polymeric network with the aim to supply ROS in situ or O2 as an alternative source for standard PDT.