Kinetically frozen copolymer nanocarriers : from non-equilibrium self-assembly to in vitro and in vivo evaluation Laurence Jennings To cite this version: Laurence Jennings. Kinetically frozen copolymer nanocarriers : from non-equilibrium self-assembly to in vitro and in vivo evaluation. Chemical Physics [physics.chem-ph]. Université de Strasbourg, 2015. English. NNT : 2015STRAE035. tel-01591164 HAL Id: tel-01591164 https://tel.archives-ouvertes.fr/tel-01591164 Submitted on 21 Sep 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. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DE PHYSIQUE ET CHIMIE-PHYSIQUE Institut Charles Sadron THÈSE présentée par : Laurence JENNINGS soutenue le : 23 Novembre 2015 pour obtenir le grade de : 'RFWHXUGHO¶XQLYHUVLWp de Strasbourg Discipline/ Spécialité : Physique et Chimie-Physique Micelles figées de copolymères séquencés: de l'auto-assemblage hors- équilibre aux comportements in vitro et in vivo THÈSE dirigée par : M. SCHOSSELER François Directeur de thèse, Université de Strasbourg M. MENDES Eduardo Codirecteur de thèse, TUDelft RAPPORTEURS : M. DURAND Alain Rapporteur externe, Université de Lorraine M. JANIER Marc Rapporteur externe, Université Claude Bernard AUTRES MEMBRES DU JURY : M. MAALOUM Mounir Examinateur interne, Université de Strasbourg Kinetically Frozen Copolymer Nanocarriers: From Non-Equilibrium Self-Assembly to in vitro and in vivo Evaluation Laurence Jennings Institut Charles Sadron, Strasbourg November 2015 Dissertation submitted to the University of Strasbourg For the degree of Doctor of Philosophy The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PITN-GA-2012-317019 'TRACE 'n TREAT'. 3 Table of Contents Table of Contents .................................................................................................................................... 5 1 Introduction ..................................................................................................................................... 7 1.1 dƌĂĐĞ͚ŶdƌĞĂƚŽŶƐŽƌƚŝƵŵ .................................................................................................. 8 1.2 Motivation and Scope ....................................................................................................... 12 1.3 Structure and Contents of the Chapters ........................................................................... 15 1.4 References ........................................................................................................................ 17 2 Spontaneous Emulsification .......................................................................................................... 19 2.1 Introduction ...................................................................................................................... 20 2.2 Results and Discussion ...................................................................................................... 24 2.3 Conclusions ....................................................................................................................... 41 2.4 Experimental Section ........................................................................................................ 43 2.5 References ........................................................................................................................ 44 3 Morphology of kinetically frozen micelles ..................................................................................... 47 3.1 Introduction ...................................................................................................................... 48 3.2 Results and Discussion ...................................................................................................... 53 3.3 Conclusions ....................................................................................................................... 62 3.4 Experimental Section ........................................................................................................ 64 3.5 References: ....................................................................................................................... 65 4 Mechanical properties of Micelles ................................................................................................ 67 4.1 Introduction ...................................................................................................................... 68 4.2 Results and Discussion ...................................................................................................... 74 4.3 Experimental Section ........................................................................................................ 81 4.4 References ........................................................................................................................ 85 5 In vitro & In vivo evaluation of spherical and elongated PS-PEO micelles .................................... 89 5.1 Introduction ...................................................................................................................... 90 5 Table of Contents 5.2 Results and Discussion ...................................................................................................... 94 5.3 Conclusions ..................................................................................................................... 107 5.4 Experimental Section ...................................................................................................... 108 5.5 References ...................................................................................................................... 113 6 Conclusions and Future Outlook ................................................................................................. 117 7 Résumé de thèse en Français ...................................................................................................... 123 7.1 Introduction .................................................................................................................... 123 7.2 La formation de micelles ................................................................................................. 124 7.3 Nouveau procédé de formation de micelles................................................................... 130 7.4 Module de flexion de micelles allongées ........................................................................ 131 7.5 Comportements in vitro et in vivo .................................................................................. 133 7.6 Conclusions ..................................................................................................................... 135 7.7 References ...................................................................................................................... 136 6 1 Introduction This introductory chapter serves the function of guiding the reader through this thesis. In the initial part there will be an overview of the consortium which this PhD project was part of. This will include a description of all the members of the consortium as well as an overview of the workflow between partners. Subsequently the motivation and scope for the formation of the consortium and specifically behind this thesis will be given. Due to the interdisciplinary nature of this project, each chapter covers a different topic, all of which belong to different fields of research. In order to facilitate the reader, each chapter begins with its own introductory section which is focused on presenting the basic scientific knowledge and references required for a comprehension of the experimental part. 7 1.1 7UDFH¶Q7UHDW&RQVRUWLXP 1.1 7UDFH¶Q7UHDW&RQVRUWLXP dƌĂĐĞ͚ŶdƌĞĂƚŝƐĂDĂƌŝĞƵƌŝĞ/ŶŝƚŝĂůdƌĂŝŶŝŶŐEĞƚǁŽƌŬ͕ĨƵŶĚĞĚďLJƚŚĞƵƌŽƉĞĂŶŽŵŵŝƐƐŝŽŶǁŝƚŚŝŶ the 7th Framework Programme that has started on October 1, 2012. The aim of the consortium is the development of molecular and supramolecular technology for nuclear imaging and radionuclide therapy that will contribute to the fight against cancer. The consortium is composed of 8 early stage researchers (ESR), PhD students, located in four different European countries: Belgium, France, Germany and The Netherlands. The academic and commercial partners of the consortium, with a brief description of their role and the number of appointed researchers are listed below: x Erasmus Medial Center ; Rotterdam, The Netherlands ʹ 1 appointed ESR o The Erasmus University Medical Center, Erasmus MC, is one of the largest University Medical Center in Europe. The development of Somatostatin Receptor-Targeted Radionuclide therapy of tumors is one of the major achievements in radiomedicine developed at Erasmus MC. [1] The fellow appointed at Erasmus MC, under the supervision of Prof. Marion de Jong, had the task of performing in-vivo studies using the micelles produced by the other fellows of the consortium. x IDB Holland from atom to image ; Baarle Nassau, The Netherlands