| Doctorant : |
Nataliya STOROZHYLOVA
|
| Directeur de thèse : |
Cyrille GRANDJEAN ,
Directeur de recherche CNRS |
| co-directeur de thèse : | Maria José Alonso Fernandez, Professeur, Université de Saint-Jacques de Compostelle, Espagne |
| Financement : |
Union européenne : Erasmus Mundus |
| Date de la soutenance : |
vendredi 18 mai 2018, 13h00 |
| Modalité : |
|
| Jury : |
- Président de jury : Jérôme Guicheux, Directeur de Recherche, INSERM, Université de Nantes
- Rapporteur : Pascal Reboul, Professeur, Université de Lorraine
- Rapporteur : Carmen Evora, Professeur, Université de La Laguna, Espagne
- Examinateur : Marco Garcia Fuentes, Assistant Professeur, Université de Saint-Jacques de Compostelle, Espagne
- Directeur de thèse :
Cyrille GRANDJEAN ,
Directeur de recherche CNRS
- co-directeur de thèse : Maria José Alonso Fernandez, Professeur, Université de Saint-Jacques de Compostelle, Espagne
|
This thesis project covers the design, development and in vivo evaluation of a novel self-assembled injectable biodegradable drug delivery system (DDS), composed of in situ hydrogel combined with nanocapsules for lipophilic anti-inflammatory drugs, aiming prolonged intra-articular (IA) residence time and controlled drug release. The moderate initial viscosity allows good syringeability, while rheological properties of the assembled DDS enable resistance to high deformations, displaying the hydrogel suitable for IA application. In this regard, to validate the new delivery system, dexamethasone was used as a model drug. Besides, a novel and potential lead compound for immunotherapeutic anti-rheumatic drug candidate – galectin-3 antagonist was synthesized, characterized and evaluated in this study. The preliminary in vivo results demonstrated remarkable suppression of acute joint inflammation by galectin-3 inhibitor encapsulated within hydrogel and administrated IA at microgram scale doses compared to non-treated control. Overall, the work presented here portrays the DDS with encapsulated synthetic galectin-3 inhibitor as a capable in situ nanotechnology-based platform for arthropathies treatment, intended to contribute to efficient joints therapies.
Publications
2020
Storozhylova, Nataliya; Crecente-Campo, José; Cabaleiro, David; Lugo, Luis; Dussouy, Christophe; Simões, Sandra; Monteiro, Madalena; Grandjean, Cyrille; Alonso, María J
An In Situ Hyaluronic Acid-Fibrin Hydrogel Containing Drug-Loaded Nanocapsules for Intra-Articular Treatment of Inflammatory Joint Diseases Article de journal
Dans: Regenerative Engineering and Translational Medicine, vol. 6, no. 2, p. 201–216, 2020, ISSN: 23644141.
@article{Storozhylova2020,
title = {An In Situ Hyaluronic Acid-Fibrin Hydrogel Containing Drug-Loaded Nanocapsules for Intra-Articular Treatment of Inflammatory Joint Diseases},
author = {Nataliya Storozhylova and José Crecente-Campo and David Cabaleiro and Luis Lugo and Christophe Dussouy and Sandra Sim{õ}es and Madalena Monteiro and Cyrille Grandjean and María J Alonso},
doi = {10.1007/s40883-020-00154-2},
issn = {23644141},
year = {2020},
date = {2020-01-01},
journal = {Regenerative Engineering and Translational Medicine},
volume = {6},
number = {2},
pages = {201--216},
publisher = {Regenerative Engineering and Translational Medicine},
abstract = {Abstract: Intra-articular (IA) administration of drugs is an appealing route for the effective treatment of large-joint diseases. However, a key limitation of this route is the premature elimination of the injected drugs from the synovial cavity. The objective of this work was to develop an easily injectable controlled release system intended to prolong the activity of anti-inflammatory drugs in the articular cavity. The system was an in situ forming hydrogel, made of fibrin and hyaluronic acid (HA), loaded with nanocapsules (NCs). The NCs, consisting of an olive oil core surrounded by a HA shell, were loaded with two different drugs, dexamethasone (DMX) and a galectin-3 inhibitor. They presented a particle size in the range of 122–135 nm and a surface charge of − 29/− 31 mV. The gelation time, rheological properties and porosity of the system could be adjusted by different parameters, such as addition of fibrin crosslinkers factor XIII and α2-antiplasmin. The non-crosslinked HA-fibrin hydrogels containing 30% (v/v) NCs showed the capacity to control the release of the encapsulated drug, DMX, for 72 h in simulated synovial fluid. The preliminary in vivo evaluation of the system containing a galectin-3 inhibitor in an acute synovitis rat model showed a suppression of inflammation after IA administration compared with the non-treated control. In brief, this work shows the possibility to combine an in situ forming hydrogel and NCs as a drug delivery strategy for IA administration and suggests its potential for the treatment of arthropathies. Lay Summary: This work describes the development and characterization of a new in situ forming hydrogel adapted for intra-articular administration of anti-inflammatory drugs. The prolonged local delivery of these drugs is expected to improve the treatment of large-joint arthropathies. To achieve this objective, the hydrogel, made of biodegradable materials, was loaded with nanodeposits of drugs, named nanocapsules. The efficacy of the system, containing a new galectin-3 inhibitor as a drug candidate, was tested in a rat model of acute synovial inflammation. These results represent the first insights on the in vivo activity of a new galectin-3 inhibitor on a potential galectin-3 immunotherapeutic target for inflammatory joints diseases. [Figure not available: see fulltext.]},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Abstract: Intra-articular (IA) administration of drugs is an appealing route for the effective treatment of large-joint diseases. However, a key limitation of this route is the premature elimination of the injected drugs from the synovial cavity. The objective of this work was to develop an easily injectable controlled release system intended to prolong the activity of anti-inflammatory drugs in the articular cavity. The system was an in situ forming hydrogel, made of fibrin and hyaluronic acid (HA), loaded with nanocapsules (NCs). The NCs, consisting of an olive oil core surrounded by a HA shell, were loaded with two different drugs, dexamethasone (DMX) and a galectin-3 inhibitor. They presented a particle size in the range of 122–135 nm and a surface charge of − 29/− 31 mV. The gelation time, rheological properties and porosity of the system could be adjusted by different parameters, such as addition of fibrin crosslinkers factor XIII and α2-antiplasmin. The non-crosslinked HA-fibrin hydrogels containing 30% (v/v) NCs showed the capacity to control the release of the encapsulated drug, DMX, for 72 h in simulated synovial fluid. The preliminary in vivo evaluation of the system containing a galectin-3 inhibitor in an acute synovitis rat model showed a suppression of inflammation after IA administration compared with the non-treated control. In brief, this work shows the possibility to combine an in situ forming hydrogel and NCs as a drug delivery strategy for IA administration and suggests its potential for the treatment of arthropathies. Lay Summary: This work describes the development and characterization of a new in situ forming hydrogel adapted for intra-articular administration of anti-inflammatory drugs. The prolonged local delivery of these drugs is expected to improve the treatment of large-joint arthropathies. To achieve this objective, the hydrogel, made of biodegradable materials, was loaded with nanodeposits of drugs, named nanocapsules. The efficacy of the system, containing a new galectin-3 inhibitor as a drug candidate, was tested in a rat model of acute synovial inflammation. These results represent the first insights on the in vivo activity of a new galectin-3 inhibitor on a potential galectin-3 immunotherapeutic target for inflammatory joints diseases. [Figure not available: see fulltext.]
2018
Dion, Johann; Storozhylova, Nataliya; Dahbi, S; Lambert, Annie; Téletchéa, Stéphane; Dussouy, Christophe; Grandjean, Cyrille
Design and screening of sugar-derived small molecule inhibitors of galectins. Proceedings Article
Dans: J. Protein Proteomics, 2018.
@inproceedings{dion2018,
title = {Design and screening of sugar-derived small molecule inhibitors of galectins.},
author = {Johann Dion and Nataliya Storozhylova and S Dahbi and Annie Lambert and Stéphane Téletchéa and Christophe Dussouy and Cyrille Grandjean},
year = {2018},
date = {2018-01-01},
booktitle = {J. Protein Proteomics},
journal = {J. Protein Proteomics},
volume = {9},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
2017
Dion, Johann; Deshayes, Frédérique; Storozhylova, Nataliya; Advedissian, Tamara; Lambert, Annie; Viguier, Mireille; Tellier, Charles; Dussouy, Christophe; Poirier, Françoise; Grandjean, Cyrille
Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair Article de journal
Dans: ChemBioChem, vol. 18, no. 8, p. 782–789, 2017, ISSN: 14397633.
@article{Dion2017c,
title = {Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair},
author = {Johann Dion and Frédérique Deshayes and Nataliya Storozhylova and Tamara Advedissian and Annie Lambert and Mireille Viguier and Charles Tellier and Christophe Dussouy and Françoise Poirier and Cyrille Grandjean},
doi = {10.1002/cbic.201600673},
issn = {14397633},
year = {2017},
date = {2017-01-01},
journal = {ChemBioChem},
volume = {18},
number = {8},
pages = {782--789},
abstract = {Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3′ positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3′ positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization.
Dion, Johann; Advedissian, Tamara; Storozhylova, Nataliya; Dahbi, Samir; Lambert, Annie; Deshayes, Frédérique; Viguier, Mireille; Tellier, Charles; Poirier, Françoise; Téletchéa, Stéphane; Dussouy, Christophe; Tateno, Hiroaki; Hirabayashi, Jun; Grandjean, Cyrille
Development of a Sensitive Microarray Platform for the Ranking of Galectin Inhibitors: Identification of a Selective Galectin-3 Inhibitor Article de journal
Dans: ChemBioChem, vol. 18, no. 24, p. 2428–2440, 2017, ISSN: 14397633.
@article{Dion2017a,
title = {Development of a Sensitive Microarray Platform for the Ranking of Galectin Inhibitors: Identification of a Selective Galectin-3 Inhibitor},
author = {Johann Dion and Tamara Advedissian and Nataliya Storozhylova and Samir Dahbi and Annie Lambert and Frédérique Deshayes and Mireille Viguier and Charles Tellier and Françoise Poirier and Stéphane Téletchéa and Christophe Dussouy and Hiroaki Tateno and Jun Hirabayashi and Cyrille Grandjean},
doi = {10.1002/cbic.201700544},
issn = {14397633},
year = {2017},
date = {2017-01-01},
journal = {ChemBioChem},
volume = {18},
number = {24},
pages = {2428--2440},
abstract = {Glycan microarrays are useful tools for lectin glycan profiling. The use of a glycan microarray based on evanescent-field fluorescence detection was herein further extended to the screening of lectin inhibitors in competitive experiments. The efficacy of this approach was tested with 2/3′-mono- and 2,3′-diaromatic type II lactosamine derivatives and galectins as targets and was validated by comparison with fluorescence anisotropy proposed as an orthogonal protein interaction measurement technique. We showed that subtle differences in the architecture of the inhibitor could be sensed that pointed out the preference of galectin-3 for 2′-arylamido derivatives over ureas, thioureas, and amines and that of galectin-7 for derivatives bearing an α substituent at the anomeric position of glucosamine. We eventually identified a diaromatic oxazoline as a highly specific inhibitor of galectin-3 versus galectin-1 and galectin-7.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Glycan microarrays are useful tools for lectin glycan profiling. The use of a glycan microarray based on evanescent-field fluorescence detection was herein further extended to the screening of lectin inhibitors in competitive experiments. The efficacy of this approach was tested with 2/3′-mono- and 2,3′-diaromatic type II lactosamine derivatives and galectins as targets and was validated by comparison with fluorescence anisotropy proposed as an orthogonal protein interaction measurement technique. We showed that subtle differences in the architecture of the inhibitor could be sensed that pointed out the preference of galectin-3 for 2′-arylamido derivatives over ureas, thioureas, and amines and that of galectin-7 for derivatives bearing an α substituent at the anomeric position of glucosamine. We eventually identified a diaromatic oxazoline as a highly specific inhibitor of galectin-3 versus galectin-1 and galectin-7.