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Synthèse Et Évaluation Pharmacologique D'analogues Préactivés De L'ifosfamide

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Synthèse Et Évaluation Pharmacologique D'analogues Préactivés De L'ifosfamide Synthèse et évaluation pharmacologique d’analogues préactivés de l’ifosfamide : prodrogues et nanoparticules à visée antitumorale Charles Skarbek To cite this version: Charles Skarbek. Synthèse et évaluation pharmacologique d’analogues préactivés de l’ifosfamide : prodrogues et nanoparticules à visée antitumorale. Pharmacie galénique. Université Paris Saclay (COmUE), 2017. Français. NNT : 2017SACLS247. tel-01618196 HAL Id: tel-01618196 https://tel.archives-ouvertes.fr/tel-01618196 Submitted on 17 Oct 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 2 REMERCIEMENTS Je voudrais exprimer mes remerciements aux membres du jury, aux rapporteurs : les Maitres de Conférences Joseph Ciccolini et Sylvie Bégu, ainsi qu’aux examinateurs : les professeurs Elias Fattal, Thierry Martens et Nathalie Chaput ainsi que les docteurs Alain Herrera et Emilie Roger, d’avoir accepté de juger mon travail de thèse. Je souhaite remercier le Dr Lluis Mir, directeur de l’unité UMR CNRS 8203 pour m’avoir accueilli dans son laboratoire « vectorologie et thérapeutiques anticancéreuses » et de m’avoir permis de réaliser mes travaux de thèse après mon stage de Master 2, au cours desquels j’ai pu développer la formulation des dérivés préactivés de l’ifosfamide et réaliser leur évaluation pharmacologique. Je tiens à exprimer ma profonde gratitude au Pr Angelo Paci, mon directeur de thèse, pour m’avoir accueilli dans l’équipe « vectorologie chimique », pour m’avoir offert l’opportunité de travailler sur un projet de recherche scientifique intéressant et pour m’avoir guidé pendant ces années de thèse. Je le remercie de m’avoir transmis ses connaissances en pharmacologie avec pédagogie ainsi que pour m’avoir encouragé pour présenter mes travaux lors de plusieurs congrès internationaux. J’adresse mes remerciements au Pr Erwan Le Gall pour son accueil au sein de son équipe « électrochimie et synthèse organique » au sein de l’institut de chimie des matériaux Paris Est (UMR CNRS 7182) et de m’avoir permis de réaliser la synthèse des analogues préactivés de l’ifosfamide durant mon stage de master 2 et mes années de thèse. Je veux adresser un grand merci au Dr Michaël Rivard, maitre de conférences, pour m’avoir transmis tout son savoir dans le domaine de la chimie organique. Je le remercie pour sa grande disponibilité pendant mes expériences de laboratoire. Je le remercie aussi pour sa contribution lors de la rédaction de mon manuscrit. Je souhaite remercier le Pr Jean-Pierre Benoit ainsi que le Dr Emilie Roger pour leur collaboration et pour la mise en œuvre des travaux d’encapsulation de certains analogues préactivés de l’ifosfamide. Je voudrais aussi remercier le Pr Nathalie Chaput et les Dr Mélanie Desbois et Dr Sophie Viaud (Laboratoire d’Immunomonitoring en Oncologie, Gustave Roussy) qui m’ont permis d’acquérir une expérience en immunologie lors des travaux sur l’étude de l’effet immunomodulateur de l’ifosfamide. Je remercie aussi plus particulièrement Julia Delahousse qui a participé grandement à cette étude. Je remercie vivement Alain Deroussent, ingénieur de recherche, qui m’a apporté ses connaissances en chimie analytique et son expertise en spectrométrie de masse. Je le remercie aussi pour sa disponibilité lors de la correction et la rédaction de mes articles ainsi que de mon manuscrit. 3 J’exprime ma sincère gratitude à l’ensemble de mes collègues de l’équipe « électrochimie et synthèse organique » et plus particulièrement au Dr Anthony Olivier ainsi qu’à Patrice Renevret qui ont tous les deux participé à la réussite de mon projet de recherche. Je tiens à remercier le Dr Eric Le Cam, Catherine Durieu et Sonia Baconnais (UMR 8126) pour leur collaboration lors de la réalisation de l’étude des nanosystèmes par microscopie électronique à transmission. Je remercie aussi le Dr Jean-Rémi Bertrand ingénieur de recherche pour avoir obtenu l’analyseur des nanoparticules par diffusion de la lumière. Je remercie également l’équipe de la « plateforme d’évaluation préclinique » de Gustave Roussy, et plus particulièrement, le Dr Karine Ser Le Roux et Mélanie Polrot pour leur contribution à plusieurs études précliniques chez la souris. Je remercie tout particulièrement le Dr Estelle Daudigeos-Dubus, Léa Lesueur, Julia Delahousse, Ludivine Le Dret, Antoine Azan, Alexandre Plessier, Atmane Seck pour leur présence, leur écoute, leur aide au quotidien dans le déroulement de mon projet de recherche ainsi que pour leur participation à mon épanouissement au sein du laboratoire. Je remercie toutes les stagiaires (Aurore, Sandra, Valentine, Déborah, Naïma...) que j’ai pu encadrer lors de mon doctorat et qui ont participé à l’avancement de ce projet de recherche. Je remercie enfin l’ensemble de l’unité « vectorologie et thérapeutiques anticancéreuses » de Gustave Roussy pour l’ambiance cordiale au sein du laboratoire. 4 TABLE DES MATIERES REMERCIEMENTS .................................................................................................... 3 ABREVIATIONS ......................................................................................................... 9 LISTE DES ILLUSTRATIONS .................................................................................. 11 1 INTRODUCTION .................................................................................................. 15 1.1 LES OXAZAPHOSPHORINES, AGENTS ALKYLANTS DE L’ADN .................................. 15 1.1.1 Historique du développement des agents alkylants ................................ 15 1.1.2 Mécanisme d’action des agents alkylants ............................................... 16 1.1.3 Généralités sur les oxazaphosphorines .................................................. 17 1.1.4 L’ifosfamide ............................................................................................. 18 1.2 LES NANOTECHNOLOGIES .................................................................................. 24 1.2.1 Généralités .............................................................................................. 24 1.2.2 Historique ................................................................................................ 25 1.2.3 Classification des nanomédecines .......................................................... 25 1.2.4 Classification selon leur composition ...................................................... 28 1.2.5 Utilisation des nanomédicaments en cancérologie ................................. 34 1.2.6 Caractérisation des nanomédicaments ................................................... 38 1.2.7 Propriétés des nanomédicaments ........................................................... 41 1.2.8 Mécanismes de ciblage .......................................................................... 45 1.2.9 La nanotoxicologie .................................................................................. 48 2 OBJECTIFS DES TRAVAUX DE THÈSE ............................................................ 53 3 ETAT DE L’ART ................................................................................................... 57 3.1 STRATÉGIES DE PHARMACOMODULATION ............................................................ 57 3.1.1 Modification du cycle oxazaphosphorine ................................................ 57 3.1.2 Modification des chaînes latérales .......................................................... 60 5 3.1.3 Modification de la moutarde alkylante ..................................................... 62 3.2 IMMUNITÉ ET CANCER ........................................................................................ 67 3.2.1 Généralités .............................................................................................. 67 3.2.2 L’immunoediting ...................................................................................... 70 3.2.3 Association chimiothérapie/immunothérapie ........................................... 72 3.2.4 Effet immunomodulateur des agents cytototoxiques ............................... 73 4 RESULTATS ........................................................................................................ 77 4.1 ANALOGUES D’IFOSFAMIDE PREACTIVES PERMETTANT LA LIBERATION DE LA MOUTARDE ISOPHOSPHORAMIDEE : SYNTHESE ET PREUVE DE CONCEPT ........................................ 77 4.1.1 Introduction de l’article ............................................................................ 77 4.1.2 Discussion de l’article ............................................................................. 80 4.2 ANALOGUES D’IFOSFAMIDE POLY-ISOPRENIQUES : AGENTS ANTITUMORAUX PREACTIVES SOUS LA FORME LIBRE OU NANOPARTICULAIRE ........................................................... 82 4.2.1 Introduction de l’article ............................................................................ 82 4.2.2 Discussion de l’article. ............................................................................ 95 4.3 ENCAPSULATION D’ANALOGUES PREACTIVES D’IFOSFAMIDE AU SEIN DE NANOCAPSULES LIPIDIQUES (NCLS). ................................................................................................
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