Leblond, Jeanne (2005) Conception, synthese, et évaluation de systemes non cationiques de vectorisation de l'ADN. PhD thesis Chimie Moleculaire, ENSCP.

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Abstract

La recherche de vecteurs non viraux pour la thérapie génique est un domaine très développé. Les systèmes cationiques montrent une forte efficacité de transfection in vitro, mais cette activité est considérablement diminuée in vivo car les complexes ADN/vecteur, du fait de leur charge globale positive, sont rapidement éliminés de la circulation sanguine. Les lipopolythiourées sont des systèmes non cationiques qui représentent une alternative aux lipides cationiques: ils permettent de réduire de moitié l'élimination précoce après une injection intraveineuse.
Dans ce mémoire est décrite la synthèse d'une famille de seize lipopolythiourées dont la structure repose sur une tête polaire branchée à deux motifs thiourée. Ces lipides présentent une grande diversité au niveau de l'ancre hydrophobe, de l'espaceur, du répartiteur et des terminaisons.
L'évaluation de cette famille a été réalisée de façon systématique et la recherche du mécanisme d'action a été entreprise. Ces études ont permis la mise au point de lipopolythiourées d'une formulation facile et possédant un pouvoir transfectant du même ordre de grandeur que celui des lipides cationiques.

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Table of content

SOMMAIRE
I. INTRODUCTION SUR LES VECTEURS DE GENES - 8
A. LA THERAPIE GENIQUE - 8
1. Principe et Résultats - 8
2. Les vecteurs viraux - 12
3. Les vecteurs non viraux - 16
B. LES VECTEURS CATIONIQUES - 21
1. Lipides cationiques - 21
2. Les polymères cationiques - 24
3. Barrières au transfert de gènes - 26
C. LES VECTEURS NON CATIONIQUES - 33
1. Vecteurs anioniques - 33
2. Les vecteurs neutres existants - 33
3. Vers un nouveau type d'interaction avec l'ADN - 37
D. LES LIPOPOLYTHIOUREES - 38
1. La fonction thiourée - 38
2. Résultats du lipide DT3TU - 40
3. Conclusion - 43
II. OBJECTIF DU TRAVAIL - 44
A. DEFINITION DU PROJET - 44
B. REALISATION - 45
1. Les éléments fixes - 45
2. Structure de la famille de lipopolythiourées - 45
3. Les éléments variables - 46
III. SYNTHESE D'UNE FAMILLE DE LIPOPOLYTHIOUREES - 48
A. GENERALITES - 48
1. Stratégie - 48
2. Réactions "clé" - 48
B. PREPARATION DES PREMIERES LIPOPOLYTHIOUREES - 50
1. Rétrosynthèse - 50
2. Synthèse des précurseurs - 52
3. Assemblage du vecteur - 54
C. VARIATION DE L'ESPACEUR ET DU REPARTITEUR - 56
1. Espaceurs succinique et diglycolique - 57
2. Espaceur PEG - 63
3. Répartiteur dissymétrique - 67
D. VARIATION DES TERMINAISONS - 70
1. Terminaison alcool - 70
2. Terminaison diol - 71
3. Terminaison méthyle - 71
4. Terminaison imidazole - 72
E. VARIATION DE L'ANCRE HYDROPHOBE - 73
1. Longueur des chaînes aliphatiques - 73
2. Ancre cholestérol - 77
F. SYNTHÈSE D'UNE THIOURÉE FLUORESCENTE - 78
1. Rétrosynthèse - 78
2. Synthèse - 80
G. CONCLUSION - 81
1. Bilan des vecteurs synthétisés - 81
2. Conclusion - 82
IV. ETUDE DES PROPRIETES PHYSICO-CHIMIQUES ET BIOLOGIQUES DES LIPOPOLYTHIOUREES SYNTHETISEES - 85
A. STRATEGIE ET METHODES - 85
1. Méthodes physico-chimiques - 85
2. Critères d'évaluation biologique - 91
B. EVALUATION DES FORMULATIONS DES LIPOPOLYTHIOUREES - 92
1. Validité du modèle - 92
2. Evaluation systématique des lipopolythiourées - 94
3. Automatisation de la formulation - 98
C. ETUDES BIOPHYSIQUES - 100
1. Accessibilité de l'ADN - 100
2. Morphologie des complexes lipopolythiourée/ADN - 101
3. Conformation de l'ADN - 102
4. Protection de l'ADN par les complexes - 104
D. EVALUATION IN VITRO - 106
1. Efficacité de transfection - 106
2. Etudes de ciblage - 109
3. Toxicité in vitro - 111
E. EVALUATION IN VIVO - 115
1. Toxicité in vivo - 115
2. Efficacité de transfection intratumorale - 116
3. Biodistribution - 116
F. CONCLUSION - 118
V. DISCUSSION - 119
A. LES LIPOPOLYTHIOUREES - 119
1. Stabilité des lipopolythiourées - 119
2. Etude de la charge des complexes - 119
3. Toxicité - 123
4. Comparaison des lipopolythiourées avec le lipide DT3TU et les systèmes cationiques - 124
B. ETUDES STRUCTURE/PROPRIETES - 125
1. Influence de l'espaceur et du répartiteur - 126
2. Influence de la terminaison - 126
3. Influence de la chaîne: famille lysine - 128
4. Influence de la chaîne: famille diglycolique - 129
C. ETUDE MECANISTIQUE - 130
1. Voie d'entrée dans la cellule - 130
2. Sortie de l'endosome - 134
D. CONCLUSION - 136
VI. CONCLUSION GENERALE ET PERSPECTIVES - 138
VII. PARTIE EXPERIMENTALE - 140
VIII. REFERENCES BIBLIOGRAPHIQUES - 191

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