A novel CyD-carrier tackling hypoxia in breast cancer: orthogonal cooperation of chemotherapy, PDT & O2-releasers

Cyclodextrin (CyD)-polymers have been demonstrated to improve the water solubility and stability of conventional hydrophobic drugs and to be able to load in a single, biocompatible platform multiple therapeutic agents for cancer treatment. Photodynamic therapy (PDT) is receiving increasing attention for the treatment of solid tumors, including Breast Cancer (BC). It consists in the administration of a photosensitizer (PS) which produces Reactive Oxygen Species (ROS) i.e. singlet oxygen (1O2), upon irradiation with red light in the presence of molecular oxygen (O2), triggering a cascade of processes eventually killing cancer cells. Yet, tumor tissues suffer a condition of inadequate supply of O2 (hypoxia) which reduces PDT efficacy and activate molecular pathways inducing resistance to chemotherapy (i.e. taxanes). The aim of the HypoCyclo project is to develop CyD-polymers i) able to load taxanes i.e. paclitaxel as chemotherapeutic agent, ii) decorated with a PS i.e. Chlorin e6 (Ce6) for standard PDT, and iii) implemented with an Oxygen Releasing Agent (ORA) that will supply O2 in situ. The result will be a novel combination of chemo- and photo-therapies for the effective treatment of BC, bypassing the limits induced by hypoxic conditions. Anthracene and naphthalene derivatives were selected as suitable ORA because of their capacity to form endoperoxides by trapping 1O2 and their exceptional ability of releasing it upon controlled cycloreversion5. The photochemical synthesis of four ORAs has been achieved after optimization of published procedures and the products were characterized by NMR, IR, UV-Vis and ESI-MS. We successfully entrapped ORA and Ce6 in βCyD-polymer, the latter with a Kb = 10^3 M-1 without affecting its ability to generate 1O2 in deuterated solution. Preliminary results will be shown regarding i) the optimized photooxygenation procedure, ii) the encapsulation and covalent link of ORAs wit