Photochemical synthesis and preliminary photophysical evaluation of a multi-component polymer enabling PDT in hypoxic conditions as novel Breast Cancer treatment

Nanotechnologies grounded on cyclodextrin (CyD)-based polymeric nanoparticles (NPs) have been accurately tailored in order to improve the pharmaco-kinetic and dynamic profiles of conventional drugs and to load in a single, biocompatible carrier multiple therapeutic agents to achieve specific tumor tissue targeting [1]. Light-activated therapies are receiving increasing attention for the treatment of solid tumors, including Breast Cancer (BC). Photodynamic therapy (PDT) consists in the administration of a photosensitizer (PS) which produces reactive oxygen species (ROS) i.e.singlet oxygen (1 O2), upon irradiation with red light in the presence of molecular oxygen (O2), triggering a cascade of processes eventually killing cancer cells. Yet, tumor cells can undergo tissue hypoxia, such as an inadequate supply of O2, which will reduce PDT efficacy [2], and activate molecular pathways inducing resistance to chemotherapy (i.e. taxanes)[3]. The HypoCyclo project aims to optimize a novel combination of chemo- and photo-therapy for the selective and effective treatment of BC. CyD-based NPs able to load taxanes will be decorated with a PS i.e. Chlorin e6 (Ce6) and implemented with an Oxygen Releasing Agent (ORA) that will supply O2 in situ [4]. We synthesized four anthracene and naphthalene derivatives known as suitable ORA because of their capacity to form endoperoxide moieties by trapping 1 O2 and their exceptional ability of releasing it upon controlled cycloreversion5 . The synthesis has been achieved after optimization of published procedures. We started to study photooxygenation conditions with 9,10-diphenylanthracene (DPA) as reference compound and the obtained product was fully characterized by NMR, IR and UV-Vis spectroscopies and ESI-MS spectrometry. In parallel, we successfully entrapped Ce6 in the CyDbased NPs with a binding constant of 103 M-1 without affecting its ability to generate 1 O2 in deuterated buffer solution. At the moment, we are optimizing the photooxygenation procedures for the synthesized derivatives as well as their encapsulation in the polymeric carrier together with Ce6. Upon co-encapsulation molecular oxygen release will be evaluated