Thésis defense by Thibaut Frachon

 

keywords

Therapeutic protein stability, therapeutic protein delivery, medical devices, triple interface, insulin, protein adsorption.


Jury members :

 

Abstract

Due to the high specificity of their interactions, proteins are increasingly used in therapy and represent a vast majority of the global pharmaceutical market. Nevertheless, these molecules are fragile and therapeutic protein stability is a major concern in pharmaceutical industry. Protein degradation and aggregation can occur at every step during production, storage, transport and delivery. In this thesis, we interrogate the possible role of intermittent wetting in protein aggregation. Intermittent wetting frequently occurs in protocols involving pumping (cavitation), agitation, and liquid handling. During intermittent wetting, the air/liquid and liquid/solid interfaces meet at a triple line or triple interface, which is a local trigger for protein aggregation because it concentrates the mechanical action of the recessing fluid on the surface adsorbed proteins. We study the effect of surface intermittent wetting on insulin aggregation. Our results demonstrate that the triple interface line, where an air/water interface meets a hydrophobic surface, allows progressive protein accumulation, and finally triggers local insulin aggregation. We also show that shear stress, alone, is not detrimental for protein stability. Additionally, Additives such as polysorbates were tested, showing that the modification of the surface tension of a protein solution impacts its ability to form aggregates. Based on this work, we propose recommendations for the design of drug delivery and preparation devices in order to limit the risk of protein aggregation at the triple interface.

Jury members :

Prof. A.Astier Hopitaux Universitaires Henry Mondor, Créteil (France) Rapporteur
Dr. D.Bazile Sanofi France, Gentilly (France) Rapporteur
Dr. S.Huille Sanofi France, Vitry-sur-Seine (France) Examiner
Prof. E.Charlaix LIPHY, CNRS, Grenoble (France) Examiner
Dr. K.Anselme IS2M, CNRS, Mulhouse (France) Examiner
Dr. J.Breton INAC, CEA-UGA, Grenoble (France) Examiner
Prof. F.Bruckert LMGP, CNRS, Grenoble INP Minatec, Grenoble (France) Thesis Director
Dr. M.Weidenhaupt LMGP, CNRS, Grenoble INP Minatec, Grenoble (France) Thesis Co-director
Dr. R.Vomscheid EVEON, Montbonnot-Saint-Martin (France) Thesis Co-director