ED Sciences Chimiques
Design of diazirine-functionalized liposomes for light-triggered drug delivery
by Lilian SARYEDDINE (Institut de Chimie & de Biologie des Membranes & des Nano-objets)
The defense will take place at 13h00 - IECB amphitheater European Institute of Chemistry and Biology, IECB 2 rue Robert Escarpit 33607 PESSAC
in front of the jury composed of
- Isabelle BESTEL - Professeure des universités - Université de Bordeaux - Directeur de these
- Astrid WALRANT - Maîtresse de conférences - Sorbonne Université - Examinateur
- Ali MAKKY - Maître de conférences - Université Paris Saclay - Rapporteur
- Simon DRESCHER - Directeur general - Phospholipid Research Center - Rapporteur
- Colin BONDUELLE - Directeur de recherche - Université de Bordeaux - Examinateur
- Jeanne LEBLOND CHAIN - Directrice de recherche - Université de Bordeaux - Examinateur
Despite improved pharmacokinetics, the efficacy of liposomal drug delivery remains limited by insufficient release of therapeutic cargo at the diseased site. Light-responsive liposomes offer a promising solution by enabling spatiotemporal control over drug delivery in response to light. Diazirine is a well-known ‘minimalist' photoreactive moiety, yet its application in liposomal drug delivery remains largely unexplored. This work establishes a proof of concept for the use of diazirine-conjugated phospholipids in liposomes and identifies the structural parameters governing bilayer stability and light-triggered cargo release. The incorporation of diazirine into phospholipid acyl chains doesn't hinder their self-assembly into liposomes. This functionalization decreases the phase transition temperature of the bilayers by ~25 °C per diazirine motif and reduces bilayer order, while improving membrane stability and cargo retention under UV light-protected conditions. Upon irradiation, diazirine-containing liposomes showed rapid cargo release without membrane rupture, suggesting formation of transient packing defects induced by photolysis products. A structure–activity study across lipids of varying acyl chain length and diazirine content showed that light-induced release depends on the balance between bilayer cohesion, phase transition temperature and photoproduct-induced membrane perturbation. In vitro and in vivo studies supported the biocompatibility and tumor accumulation of diazirine-functionalized liposomes. Formulations containing diazirine-conjugated phospholipids, mixed with cholesterol and DSPE-PEG, revealed a trade-off between stability and triggerability. Preliminary studies on the encapsulation and controlled release of doxorubicin were very promising. Overall, these results identify diazirine as an effective phototrigger in light-responsive liposomes and highlights key design considerations for the development of future formulations. Key words: diazirine, liposomes, photo-responsive, light-triggered release, drug delivery