In this grant application, I propose to investigate in-depth the potential of novel inert Ru(II) polypyridyl complexes as novel anticancer drug candidates. Such compounds were investigated by Dwyer and Shulman in 1950s and 1960s both in vitro and in vivo with relatively promising results. This impressive seminal work was unfortunately not followed-up. This lack of additional studies was recently attributed, at least in part, to the observed neurotoxicity of the complexes. Nonetheless, over the last years, there has been a revival of important in vitro studies of such inert Ru(II) polypyridyl complexes for anticancer purposes. However, without further in vivo studies, it is reasonable to think that similar neurotoxicity to that observed by Dwyer and Shulman could be encountered. In order to tackle these (potential) drawbacks, I propose to use a prodrug approach. Furthermore, I also intend to investigate the potential of inert Ru(II) polypyridyl complexes as photosensitizers (PSs) in photodynamic therapy (PDT). In the search for an alternative approach to chemotherapy, PDT has proven to be a promising, effective and non-invasive treatment modality. Importantly, in order to increase even further the potential of the PSs presented in this project, I propose to also excite them via simultaneous two-photon absorption (TPA) in the so-called two-photon excitation PDT (2 PE-PDT). Importantly, the newly Ru(II)-based PSs will be coupled to cancer cell-specific peptides or antibodies. This double selectivity (targeting vector and photo-activation) should limit the frequently encountered side-effects of (metal-based) anticancer drugs. Another important aim of this second part of this project will be the use of the Ru(II)-based PSs to kill bacteria. Interestingly, PDT has been recently shown to be an interesting alternative to fight bacteria. I therefore intend to couple Ru(II)-based (2PE )PSs to bacteria-specific peptides to bring bacteria specificity.

The present proposal aims to enhance the competences, the scientific and innovative potential of the experienced researcher in the field of the emerging non-invasive treatment of a variety of cancer tumour types called photodynamic therapy (PDT). This approach induces tumour cells necrosis and/or apoptosis by a combination of a photosensitising drug (PS) capable of absorbing within the body’s therapeutic window (620–850 nm), a light source (e.g.,a laser) of an appropriate wavelength and molecular oxygen. To further advance the novel PDT treatment, the design, synthesis and characterisation of new photosensitizers with improved efficiency and side effect profiles is needed, together with a more thorough and integrated understanding of the multitude of targets/actions so far ascribed to PDT. In this field, the information that can be gained from modern theoretical methods is very useful, since several crucial chemical and physical properties of candidate photosensitizers can be accurately predicted from first principles by various computational techniques, contributing to increase the understanding of the entire photochemical pathways involved. The “a priori” knowledge of a series of properties can be considered a basic requirement before proceeding to the synthesis, chemical-physical characterisation and in vitro and in vivo tests, thus orienting experimental planning and avoiding expensive and time-consuming experiments. The project attempts to investigate members of a novel and very interesting class of bioactive molecules of interest as anti-cancer agents, consisting of a light-absorber chromophore (PS) and a cisplatin-like unit. The two-component conjugates combine the cytostatic activity of the platinum moiety in the dark, and upon irradiation, the photodynamic action of the sensitizer. Such systems could address the restrictions of Pt-based complexes and provide a target for PDT agents, while maintaining efficient DNA binding and photocleaving properties.

Due to their unique properties, the demand of synthetic biodegradable polymers as alternative environmentally friendly polymers compared to polyolefins, increases regularly. The remaining problem is the cost of such well defined biodegradable polymers such as polyesters or polyamides, especially because of the cost and poor availability of the starting material. The metal-catalysed alternative copolymerisation of heterocycles and carbon monoxide is a synthetic route of choice for the preparation of polyesters and polyamides from cheap and available monomers. Unfortunately, only a few efficient catalysts, based on cobalt and basic ligand systems, have been described yet. The ambition of the project is to study and develop more elaborated and efficient catalyst to develop and promote a cheap, efficient and industrially viable methodology for the preparation of biodegradable polymers. The first objective of the project will be to develop a large family of potential trans-diphosphine ligands, possessing different electronic and steric properties and then to prepare the corresponding complexes of cobalt and iron. Thanks to their unique properties, chelating trans-diphosphines look very judicious and promising to solve the problems encountered during the copolymerisation (i.e.: catalyst stability, decoordination of the ligand, possible side-reactions). Indeed, trans-diphosphine will stabilise and govern the properties of the catalyst giving a more stable productive and selective system. Beside, this type of ligand is the center of numerous studies in carbonylation reaction such as hydroformylation, carbonylation of olefins… Homogeneous polymerisation results in polymer contamination by metal residues and loss of catalyst, thus there is a considerable interest in developing catalyst based on iron, because of its low cost, biocompatibility and low bio-toxicity. In order to achieve efficient control of the catalytic process, the mechanism and kinetics of the reaction will be investigated as well as systematic structure reactivity studies of the ligand system. Then, attention will be paid to the copolymerisation of CO/heterocycles initiated by our cobalt and iron disphosphine complexes. We will first focus on the copolymerisation of known monomers such as epoxide and aziridine and on optimisation of reaction conditions. Another interesting part of the project will be to use our best systems for the copolymerisation of new monomers, to develop and characterize new materials. Stereoselective copolymerisation with chiral complexes will be an extremely motivating and challenging part for the project as well as the development and characterisation of new materials. By using the catalysts prepared in this project, efficient synthetic method and bio(co)polymers with original properties should result and open new avenues for an industrially viable preparation of biodegradable polymers.

In this project, I plan to use cyclometalated Ru(II) polypyridyl complexes as novel photosensitizers (PSs) in photodynamic therapy (PDT) to fight cancer. Such compounds are easier to synthesise than the well-known porphyrins and have a higher lipophilicity (to better cross the cell membrane) and a bathochromic shift of the absorption (to irradiate at low energies) than the usual Ru(II) polypyridyl complexes. Furthermore, I plan to couple maleimide moieties to these complexes to directly bind cysteine-containing biomolecules (i.e. HSA) and therefore, overcome the selectivity issues observed for the typical PSs. The use of bisbenzimidazoles as ancillary ligands will allow to tune the properties of the complexes in view of having the most red-shifted absorption. Computational chemistry will be first used to design the complexes, and after the synthesis and complete characterization, biological experiments will be performed to evaluate their potential as PSs. A secondment under the supervision of Prof. Clotilde Policar will allow localizing the compounds prepared by the use of a synchrotron-based imaging technique (X-ray fluorescence) as well as single cell ICP-MS, which will help to detect the metal inside the cell and figure out the biodistribution of the complexes. The multidisciplinary scope of this work along with their innovative aspects to selectively cause death of cancerous cells, make it a ground-breaking proposal. In addition, working in one of the best universities of the world, under the supervision of Dr. Gilles Gasser and Prof. Clotilde Policar will promote my scientific career.

Nearly 250,000 women are diagnosed each year with ovarian cancer around the world, resulting in 140,000 deaths. High-grade epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer, ranking fifth overall in cancer deaths. The majority of women have widespread intra-abdominal disease at the time of diagnosis, and the 5-year survival rate for these women is only about 40% after receiving standard therapy. Currently, the standard first-line treatment for ovarian cancer consists of surgical cytoreduction and platinum-based chemotherapy. Although this approach has proven to be the most effective treatment to date, many ovarian cancers exhibit primary platinum resistance, and most patients develop secondary platinum resistance during the course of their disease. There is therefore a paucity of approved targeted therapies. Accordingly, effective novel therapies are needed to improve survival rates for patients diagnosed with ovarian cancer, especially in its advanced stages and in the setting of platinum resistance. The phenomenal success of cisplatin, oxaliplatin and carboplatin has boosted the research directed at novel metal-based anticancer drugs. My group has embarked a few years ago into a program to thoroughly investigate Ru compounds as anticancer drug candidates. However, one serious problem of metal-based drugs is often their intrinsic toxicity. To tackle this issue and circumvent these limitations, macromolecular delivery systems can be used to improve the potential of the respective anticancer ruthenium complexes. During the frame of the ERC consolidator grant PhotoMetMed, my group could demonstrate that an innovative drug-initiated polymerization methodology could be used to tackle this problem. In this proposal, to further demonstrate that this technology could be used on human, the in vivo efficacy of this system will be validated in several in ovarian cancer Patient-Derived Xenografts (PDXs) models.