Soutenance de thèse d'Ioanna Christodoulou EN VISIOCONFERENCE
THESE : A comprehensive study of the erosion mechanism of porous hybrid particles for biomedical applications
Ioanna Christodoulou
ISMO
Hybrid porous particles named Metal Organic Frameworks nanoparticles (MOFs) are promising candidates for the delivery of active molecules in the biomedical field. Among a large variety of MOFs, the micro/mesoporous iron (III) trimesate MIL-100(Fe) (MIL stands for Materials of Lavoisier Institute) are the particles of choice, thanks to : i) their high drug payloads (up to 30 wt%) of both hydrophilic and hydrophobic drugs ; ii) their controlled release properties ; iii) convenient surface modifications and (iv) biocompatible and biodegradable nature. Once administered in the living organism, MOFs should present a good stability during circulation, until they reach their target. Once targeting is achieved, they should degrade and release their cargo, without inducing any cytotoxicity in the body. This thesis focus on the study of the fine balance between stability and degradation, through in depth investigations of the degradation mechanisms.
While MIL-100(Fe) particles are stable in aqueous and ethanolic solutions, they are rapidly degraded under simulated physiological conditions, releasing a significant amount of their constitutive trimesate ligand. More precisely, when MOFs are incubated in phosphate buffer saline (PBS), phosphate ions strongly coordinate to the iron (III) acid Lewis sites of the framework, initiating degradation. Previous studies showed that MOFs degrade without size modifications and that they have a pH and degradation-dependent aggregation. It is therefore of main interest to study the influences of the main parameters involved in MOFs degradation (the pH of the media, the size and the presence of defaults in the crystalline structures, the presence of loaded drugs in the pores and/or the presence of coating layers). The primary objective of this thesis was the rigorous study of these parameters to gain a deeper vision of the MIL-100(Fe) MOF degradation mechanisms. To do so, first, MOFs crystals of around 50 μm (microMOFs) of different crystallinity degrees were successfully synthesized and studied by an innovative in situ technique. AFM in liquid was the method of choice to follow in real time and at nanoscale resolution, morphological, dimensional and mechanical changes of microMOFs surface in media of different compositions and upon in situ modification of the pH. This method proved to be a powerful tool by highlighting some of the main parameters attributed to MOFs degradation (pH of the media, size and crystallinity degree of the particles). It paved the way for further studies of smaller particles (nanoMOFs), mainly used in drug delivery applications. In situ ellipsometry was selected to study the degradation mechanism of thin films of nanoMOFs, fabricated by a dip coating process. The developed in situ technique was used to analyze the interactions of MIL-100(Fe) nanoMOFs with the external medium (PBS with or without protein) at undersaturated conditions to mimic the in vivo conditions of the organism. After having explored the important parameters that regulate the degradation of empty micro- and nanoMOFs, a series of drugs containing different functional groups was chosen as molecules of interest for the study of host-guest interactions with the nanoMOFs. The affinity of the groups with the iron sites of the framework were assessed by Density Functional Theory (DFT) modelling, which helped to gain a better understanding over the intermolecular interactions, crucial parameters for the stability of the particles. Overall, the sum of techniques used for this thesis brought new insights into the degradation mechanism of iron-based carboxylate porous particles for their use as therapeutic vectors.
Site de l'ISMO pour obtenir le lien :
http://www.ismo.universite-paris-saclay.fr/spip.php?article2477
THESE : A comprehensive study of the erosion mechanism of porous hybrid particles for biomedical applications
Ioanna Christodoulou
ISMO
Hybrid porous particles named Metal Organic Frameworks nanoparticles (MOFs) are promising candidates for the delivery of active molecules in the biomedical field. Among a large variety of MOFs, the micro/mesoporous iron (III) trimesate MIL-100(Fe) (MIL stands for Materials of Lavoisier Institute) are the particles of choice, thanks to : i) their high drug payloads (up to 30 wt%) of both hydrophilic and hydrophobic drugs ; ii) their controlled release properties ; iii) convenient surface modifications and (iv) biocompatible and biodegradable nature. Once administered in the living organism, MOFs should present a good stability during circulation, until they reach their target. Once targeting is achieved, they should degrade and release their cargo, without inducing any cytotoxicity in the body. This thesis focus on the study of the fine balance between stability and degradation, through in depth investigations of the degradation mechanisms.
While MIL-100(Fe) particles are stable in aqueous and ethanolic solutions, they are rapidly degraded under simulated physiological conditions, releasing a significant amount of their constitutive trimesate ligand. More precisely, when MOFs are incubated in phosphate buffer saline (PBS), phosphate ions strongly coordinate to the iron (III) acid Lewis sites of the framework, initiating degradation. Previous studies showed that MOFs degrade without size modifications and that they have a pH and degradation-dependent aggregation. It is therefore of main interest to study the influences of the main parameters involved in MOFs degradation (the pH of the media, the size and the presence of defaults in the crystalline structures, the presence of loaded drugs in the pores and/or the presence of coating layers). The primary objective of this thesis was the rigorous study of these parameters to gain a deeper vision of the MIL-100(Fe) MOF degradation mechanisms. To do so, first, MOFs crystals of around 50 μm (microMOFs) of different crystallinity degrees were successfully synthesized and studied by an innovative in situ technique. AFM in liquid was the method of choice to follow in real time and at nanoscale resolution, morphological, dimensional and mechanical changes of microMOFs surface in media of different compositions and upon in situ modification of the pH. This method proved to be a powerful tool by highlighting some of the main parameters attributed to MOFs degradation (pH of the media, size and crystallinity degree of the particles). It paved the way for further studies of smaller particles (nanoMOFs), mainly used in drug delivery applications. In situ ellipsometry was selected to study the degradation mechanism of thin films of nanoMOFs, fabricated by a dip coating process. The developed in situ technique was used to analyze the interactions of MIL-100(Fe) nanoMOFs with the external medium (PBS with or without protein) at undersaturated conditions to mimic the in vivo conditions of the organism. After having explored the important parameters that regulate the degradation of empty micro- and nanoMOFs, a series of drugs containing different functional groups was chosen as molecules of interest for the study of host-guest interactions with the nanoMOFs. The affinity of the groups with the iron sites of the framework were assessed by Density Functional Theory (DFT) modelling, which helped to gain a better understanding over the intermolecular interactions, crucial parameters for the stability of the particles. Overall, the sum of techniques used for this thesis brought new insights into the degradation mechanism of iron-based carboxylate porous particles for their use as therapeutic vectors.
Site de l'ISMO pour obtenir le lien :
http://www.ismo.universite-paris-saclay.fr/spip.php?article2477