Optimisation of arene-ruthenium complexes for photodynamic therapy

Photodynamic therapy (PDT) is a two-stage treatment that requires three elements: light, a photosensitiser (PS) and oxygen so as to destroy cancerous and precancerous cells. When the PS is exposed to specific wavelengths of light, it becomes activated from a ground to an excited state. As it returns to the ground state, it releases energy, which is transferred to oxygen to generate reactive oxygen species (ROS), like singlet oxygen and free radicals. These ROS mediate cellular toxicity. PDT is used to treat a variety of diseases, including acne, psoriasis, age-related macular degeneration, and several types of cancer. PDT can be limited by different factors, like non-homogeneous distribution of the PS within the tumour after administration, low availability of oxygen within the tissue that is targeted by PDT (hypoxia), high nutrients’ supply at the tumour site, the interval between the PS administration and the tissue’s exposure to light, the selected site of the PDT action within a cell (mitochondria, plasma membrane, lysosomes, Golgi apparatus, endoplasmic reticulum, or nuclei), prolonged light sensitivity of the treated area, or even the cost of the PS, to name some of them. Many polycyclic aromatic hydrocarbons are able to trap singlet oxygen 1O2. Some of the endoperoxides (EPOs), thus obtained, exhibit the exceptional feature of releasing oxygen, frequently in the excited singlet state, upon heating or UV irradiation.1 Anthracene is such an example of a highly reversible photochromic system and has already been investigated for its ability to form EPOs and transport oxygen to cancer sites.1,2 Thus, offering a strategy to overcome one limitation of PDT treatments. Therefore, with the aim to optimise the PDT efficiency, we have focused our research on developing new and more performant PDT agents that can deal with hypoxia on the tumour site with EPOs’ onsite generation, and that can target different tissue types based on the wavelength in which each PS absorbs. In this thesis, we present the development of functionalised, monocationic, anthracenyl-areneruthenium complexes and their derivatives with porphyrins, and further functionalised arenes for ruthenium complexes and dimers. In addition, new PDT agents have been synthesised incorporating different porphyrins (TPyP, DPhDPyP, and TPhMPyP) coordinated to arene ruthenium units. All new complexes have to be tested in vitro by biologists, and some of the results are presented here.

Members of the jury:
Prof. Dr Bruno Therrien – PhD thesis director, University of Neuchâtel, Switzerland
Prof. Dr Stephan H. von Reuss – Internal examiner, University of Neuchâtel, Switzerland
Prof. Dr Bernhard Spingler – External examiner, University of Zurich, Switzerland
Thesis defended on the 26th of November 2024

No thesis : 3197