Project title: New anti-inflammatory and pro-apoptotic photosensitizers against arthritis and synovial sarcoma
Employer: University of Neuchâtel (UNINE, Switzerland), Cotutelle: University of Limoges (UNILM, France)
Supervisors: Pr. Bruno THERRIEN (UNINE), Pr. Bertrand LIAGRE (UNILIM), Dr. David LEGER (UNILIM)
Research secondments: Trinity College of Dublin, University of St Andrews, PorphyChem
Practical rotation: PorphyChem
Research project description and main objectives: Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by chronic synovitis, synoviocyte proliferation and, in its later stages, cartilage and bone destructions. When persistent, synovitis remains resistant to treatment by anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and intra-articular corticosteroids. Therefore, surgical removal of synovium is generally required and is not always efficient. In this context, we will design new functionalized arene ruthenium porphyrin or chlorin complexes in RA models. The combination of the photodynamic action of porphyrin with the cytotoxicity of arene ruthenium complexes has shown excellent anticancer activities under light. The main objective of this project is to provide new functionalized arene ruthenium porphyrin or chlorin complexes which will be tested in vitro on cultured synoviocytes isolated from fresh synovial biopsies obtained from RA patients undergoing arthroplasty and in vivo on rat models.
The main task will consist on preparing multifunctional linkers to combine arene ruthenium units and porphyrin or chlorin moieties and to study the chemical and photodynamic properties of the new compounds.
In vitro studies will demonstrate the pro-apoptotic and/or anti-inflammatory properties of the new compounds, as well as giving details on the signaling pathways activated in the treated cells. In vivo, collagen-induced RA models will help to demonstrate the safety and efficacy of the new metal-based drugs and to gain a better understanding of the biological distribution and the mode of action of these arene ruthenium photosensitizers in biological environments.
He started his career as a laboratory technician working at the University of Seville (Spain) and later at the Coca-Cola Company. After that he enrolled in the Bachelor Degree in Chemistry (2012-2016) of the University of Seville and after completing a Master’s degree in Advanced Chemistry Studies (2016-2017) at the same university, working in the group of Professor Juan Cámpora, with Professor Antonio Rodríguez Delgado as supervisor, performing a research on synthesis and characterization of organometallic complexes of aluminium, magnesium and zinc, supported by tridentate ligand based on the bis(imino)pyridine unit. Upon completion of the Master’s degree, he received a scholarship to work as Research Intern in the Okinawa Institute of Science and Technology, OIST (Japan), in the Coordination Chemistry and Catalysis Unit, under the supervision of Dr. Julia Khusnutdinova and Dr. Orestes Rivada Wheelaghan. There he did a research about organometallic ruthenium complexes stabilized by naphthyridinone ligands, for use as catalysts in dehydrogenation of alcohols and activation of small molecules (January – July, 2018).
- Photosensitizers used in the Photodynamic Therapy of Rheumatoid Arthritis, M. Gallardo-Villagran, D.Y. Léger, B. Liagre, B. Therrien, International Journal of Molecular Sciences, July 2019, DOI: 10.3390/ijms20133339
- M. Gallardo-Villagrán, L. Paulus, Y. Champavier, D.Y. Leger, B. Therrien, B. Liagre, Combination of tetrapyridylporphyrins and arene ruthenium (II) complexes to treat synovial sarcoma by photodynamic therapy, J. Porphyrins Phthalocyanines 2022, DOI: 10.1142/S1088424622020011
- M. Gallardo-Villagrán, L. Paulus, J-L Charissoux, S. Sutour, P. Vergne-Salle, D.Y. Leger, B. Liagre, B. Therrien, Evaluation of Ruthenium-Based Assemblies as Carriers of Photosensitizers to Treat Rheumatoid Arthritis by Photodynamic Therapy, Pharmaceutics 2021, 13, 2104. doi.org/10.3390/pharmaceutics13122104
- Manuel attended the Metals in Medicine workshop in Paris in November 2019
- Manuel’s covid-19 interview: