Mme Janske NEL - nouvelle docteure de l'Université d'AngersIBS, 12h30
The March 1, 2019
Titre : Lipid nanocapsules as a theranostic tool
Directeur de Thèse: Dr Laurent LEMAIRE
Co-directrice de thèse : Pr Bernard GALLEZ
Abstract:
Hypoxia is one of the most challenging aspects of the tumour microenvironment. The phenomenon occurs due to abnormal vasculature and an exacerbated metabolism, and leads to highly malignant cells resistant to radio-and cyto-toxic therapy. As such, hypoxia is of major concern and prompted our novel approach in using lipid nanocapsules (LNCs) as an oxygen sensor. LNCs have been demonstrated as excellent core-shell nanocarriers, capable of encapsulating drugs within their lipidic core and avoiding the immune system due to their PEGylated shell, thus enabling treatment of highly aggressive tumours. We hypothesised that the lipidic-core of LNCs could also be used to assess the O2 environment in tissue. Indeed, because O2 solubility is greater in lipids than in water, any subtle changes in tissue O2 will be heightened in the lipidic LNC core. Consequently, we encapsulated a lipophilic paramagnetic probe, e.g. tetrathiatriarylmethyl (TAM), and demonstrated its response to variations in O2 in vitro, using Electron Paramagnetic Resonance (EPR), indicating the permeability of LNCs to O2. We applied the TAM-LNCs to an in vivo normal tissue model (gastrocnemiusmouse muscle) and pathological model (sarcoma tumour). Herein, free TAM was rapidly reduced and no O2 measurement was possible, however, our TAM-LNC system exhibited a half-life of over an hour and enabled real-time measurements whilst animals were breathing air and during a carbogen gas (95 % O2, 5 % CO2) breathing challenge. Moreover, the lipidic-core nature of the LNCs was exploited to image tissue oxygenation using Magnetic Resonance Imaging (MRI), specifically the MOBILE sequence which enabled the mapping of O2-induced T1 relaxation rate changes in lipids. Using a single dose of LNCs, we were able to portray the change in T1between air breathing and the carbogen challenge, and image the heterogeneous nature of hypoxia in murine normal tissue and pathological tumour models. In conclusion, we demonstrated the feasibility of using LNCs as a diagnostic tool for assessing hypoxia in both normal and pathological tissues
Key words:
hypoxia; lipid nanocapsules; electron paramagnetic resonance; magnetic resonance imaging
