ED Sciences Chimiques
Biomimetic lipopolymers and stimuli-responsive lipids to tailor membrane permeability
by Rosanna LE SCOUARNEC (Acides nucléiques : Régulations Naturelles et Artificielles)
The defense will take place at 9h00 - Amphi CRPP Centre de Recherche Paul Pascal (CRPP) 115 Avenue Schweitzer 33600 Pessac
in front of the jury composed of
- Jeanne LEBLOND CHAIN - Chargée de recherche - Université de Bordeaux - Directeur de these
- Andreas HEISE - Professor - Royal College of Surgeons - Rapporteur
- Paola LUCIANI - Full professor - University of Bern, Switzerland - Rapporteur
- Colin BONDUELLE - Directeur de recherche - Université de Bordeaux - CoDirecteur de these
- Martina STENZEL - Professor - University of New South Wales - Examinateur
- Jean-Christophe BARET - Professeur - Université de Bordeaux - Examinateur
Transmembrane transport of solutes is a critical feature to build synthetic cells or to develop therapeutic nanocarriers for nanomedicine. In Nature, the diffusion across the cellular membrane is either facilitated by proteins or by unique lipid dynamics. In order to achieve improved control over permeability in cell-like compartments, synthetic systems, such as those based on polypeptides, are particularly promising. These polymers possess similar properties to proteins, including their capacity to self-assemble via well-defined secondary structures, as well as stimuli-responsive properties, biocompatibility, and biodegradability. Anchoring these polymers in a cell membrane can be facilitated by lipid functionalization. Indeed, lipids represent an alternative strategy to generate membrane destabilization through the successful development of new stimuli-responsive lipids. Whether they are polymers or lipids, their common goal is to enhance their robustness while maintaining the reactivity and reversibility of their natural counterparts. This PhD thesis investigates the synthesis of polypeptides and switchable lipids, with a particular focus on their ability to provide stimuli-responsiveness to liposomes, i.e. thermoresponsiveness. The goal of the project was to mimic membrane transport processes mediated by phospholipid or protein membrane dynamics. We first designed lipid-polyproline conjugates in order to anchor them within liposomes' membrane. Once inserted, the conjugates induced reversible phase separation in a temperature-dependent manner. Such membrane modifications resulted in liposome permeability at different scales (micro- and nanoscale) and allowed the release of cargo molecules up to the size of proteins. These polymers were then combined with pH-switchable lipids to obtain vesicles whose permeability can be modulated by several stimuli. We then designed new switchable lipid structures responsive to metal cations, whose influence on membrane permeability was investigated.